Peptide compound and its preparation

ABSTRACT

Novel peptides of the formula (I&#34;)  (* CHEMICAL STRUCTURE *) (I&#34;) in which R1 is hydrogen or acyl, R2c is lower alkyl, R3c is optionally N-substituted indolylmethyl, R4 is hydrogen, lower alkyl, C6-10 ar(lower)alkyl, amino(lower)alkyl, protected amino (lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl or optionally substituted heterocyclic (lower)alkyl, R5 is carboxy, protected carboxy, carboxy(lower)alkyl or protected carboxy(lower)alkyl, R7 is hydrogen or lower alkyl, and A is -O-, -NH-, lower alkylamino or lower alkylene, or a pharmaceutically acceptable salt thereof are disclosed. Additionally, the preparation of such peptides is described. The peptides are used to treat endothelin mediated diseases such as hypertension.

The present invention relates to new peptide compound and apharmaceutically acceptable salt thereof.

More particularly, it relates to new peptide compound and apharmaceutically acceptable salt thereof which have pharmacologicalactivities such as endothelin antagonistic activity and the like, toprocesses for its preparation, to a pharmaceutical compositioncomprising the same, and to a method of using the same therapeuticallyin the treatment and the prevention of endothelin mediated diseases suchas hypertension, and the like.

One object of the present invention is to provide new and useful peptidecompound and a pharmaceutically acceptable salt thereof which havepharmacological activities such as endothelin antagonistic activity andthe like.

Another object of the present invention is to provide processes for thepreparation of said peptide compound and a salt thereof.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said peptide compoundor a pharmaceutically acceptable salt thereof.

Still further object of the present invention is to provide a method ofusing the same for the treatment and the prevention of endothelinmediated diseases such as hypertension, and the like.

The object compound of the present invention can be represented by thefollowing general formula (I). ##STR2## in which

R¹ is hydrogen or acyl,

R² is lower alkyl, optionally substituted ar(lower)alkyl,cyclo(lower)alkyl(lower)alkyl or optionally substitutedheterocyclic(lower)alkyl,

R³ is optionally substituted heterocyclic(lower)alkyl or optionallysubstituted ar(lower)alkyl,

R⁴ is hydrogen or optionally substituted lower alkyl,

R⁵ is carboxy, protected carboxy, carboxy(lower)alkyl or protectedcarboxy(lower)alkyl,

R⁶ is hydrogen or optionally substituted lower alkyl,

R⁷ is hydrogen or lower alkyl, and

A is --O--, --NH--, lower alkylimino or lower alkylene,

provided that when R² is (S)-isobutyl, R³ isN-(dichlorobenzyloxycarbonyl)indol-3-ylmethyl, R⁴ is methyl, R⁵ ismethoxycarbonyl, R⁶ is hydrogen, R⁷ is hydrogen and A is --NH--, thenthe partial formula: ##STR3## has the absolute configuration of ##STR4##

Particularly, the compound represented by the following formula (I') ismore useful as an endothelin antagonist and the like. ##STR5## in whichR¹, R², R³, R⁴, R⁵, R⁶, R⁷ and A are each as defined above.

Further, the compound (I) having the most potent activities can berepresented by the following formula. ##STR6## in which

R¹, R⁴, R⁵, R⁷ and A are each as defined above, and

R² _(c) is lower alkyl, and

R³ _(c) is optionally N-substituted indolylmethyl.

According to the present invention, the new peptide compound (I) and asalt thereof can be prepared by the processes as shown in the followingschemes. ##STR7## in which

R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and A are each as defined above,

R¹ _(a) is acyl substituted by a protected amino group,

R¹ _(b) is acyl substituted by an amino group,

R¹ _(c) is acyl,

R² _(a) and R³ _(a) are each protected imino containingheterocyclic(lower)alkyl optionally substituted by suitablesubstituent(s),

R⁴ _(a) is protected amino(lower)alkyl or protected imino containingheterocyclic(lower)alkyl optionally substituted by suitablesubstituent(s),

R² _(b) and R³ _(b) are each imino containing heterocyclic(lower)alkyloptionally substituted by suitable substituent(s),

R⁴ _(b) is amino(lower)alkyl or imino containingheterocyclic(lower)alkyl optionally substituted by suitablesubstituent(s),

R⁴ _(c) is protected carboxy(lower)alkyl,

R⁴ _(d) is carboxy(lower)alkyl,

R⁵ _(a) is protected carboxy or protected carboxy(lower)alkyl,

R⁵ _(b) is carboxy or carboxy(lower)alkyl,

R⁵ _(c) is carboxy or esterified carboxy, and

R⁵ _(d) is amidated carboxy.

Some of the starting compounds used in the above Processes are novel andcan be prepared according to the following Methods and/or by theprocedures described in the following Preparations or by a conventionalmanner. ##STR8## in which

R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and A are each as defined above,

R⁸ is amino-protective group, and

R⁹ is protected carboxy.

Throughout the present specification, the amino acids, peptides,protective groups, condensing agents, etc. are indicated by theabbreviations according to the IUPAC-IUB (Commission on BiologicalNomenclature) which are in common use in a field of this art.

Moreover, unless otherwise indicated, the amino acids and their residueswhen shown by such abbreviations are meant to be L-configured compoundsand residues, while the D-configured compounds and residues are shownwith the prescript of D-.

Suitable pharmaceutically acceptable salts of the object compound (I)may be a conventional non-toxic salt and include an acid addition saltsuch as an organic acid salt (e.g. acetate, trifluoroacetate, maleate,tartrate, fumarate, methanesulfonate, benzenesulfonate, formate,toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride,hydrobromide, hydriodide, sulfate, nitrate, phosphate, etc.), or a saltwith a base such as an amino acid (e.g. arginine, aspartic acid,glutamic acid, etc.), an alkali metal salt (e.g. sodium salt, potassiumsalt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesiumsalt, etc.), an ammonium salt, an organic base salt (e.g. trimethylaminesalt, triethylamine salt, pyridine salt, picoline salt,dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), or thelike.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention includes within the scope thereof are explained indetail as follows.

The term "lower" is intended to mean 1 to 6, preferably 1 to 4 carbonatoms, and the term "higher" is intended to mean more than 6, preferably7 to 12 carbon atoms, unless otherwise indicated.

Suitable "acyl" may include an aliphatic acyl, an aromatic acyl, aheterocyclic acyl and an aliphatic acyl substituted with aromatic orheterocyclic group(s) derived from acids such as carboxylic, carbonic,carbamic, sulfonic acids.

The aliphatic acyl may include saturated or unsaturated, acyclic orcyclic ones, such as carbamoyl, lower alkanoyl (e.g. formyl, acetyl,propionyl, butyryl, isobutyryl, 3,3-dimethylbutyryl,4,4-dimethylvaleryl, valeryl, isovaleryl, pivaloyl, hexanoyl,3-methylvaleryl, etc.), lower alkanesulfonyl (e.g. mesyl,ethanesulfonyl, propanesulfonyl, etc.), lower alkoxycarbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,t-butoxycarbonyl, etc.), lower alkenoyl (e.g. acryloyl, methacryloyl,crotonoyl, etc.), (C₃ -C₇)cycloalkanecarbonyl (e.g. cyclohexanecarbonyl,etc.), (C₃ -C₇)cycloalkyl(lower)alkanoyl (e.g. cyclohexylacetyl, etc.),amidino, protected carboxycarbonyl such as lower alkoxalyl (e.g.methoxalyl, ethoxalyl, t-butoxalyl, etc.), C₃ -C₇ cycloalkyloxycarbonyl(e.g. cyclohexyloxycarbonyl, etc.), (heterocyclic acyl)(lower)alkanoyl,wherein said heterocyclic acyl being the same as those mentioned below,such as morpholinocarbonyl(lower)alkanoyl (e.g.3-morpholinocarbonylpropanoyl, etc.), lower or higher alkylcarbamoyl(e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,isopropylcarbamoyl, butylcarbamoyl, 2-methylbutylcarbamoyl,pentylcarbamoyl, 1,3-dimethylbutylcarbamoyl hexylcarbamoyl,hepthylcarbamoyl, octylcarbamoyl, nonylcarbamoyl, etc.),di(lower)alkylcarbamoyl (e.g. N-methyl-N-ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl,diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl,dihexylcarbamoyl, etc.), C₃ -C₇ cycloalkylcarbamoyl (e.g.cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl,cyclohexylcarbamoyl, cycloheptylcarbamoyl, etc.), N-lower alkyl-N-(C₃-C₇)cycloalkylcarbamoyl (e.g. N-methyl-N-cyclopropylcarbamoyl,N-methyl-N-cyclohexylcarbamoyl, N-ethyl-N-cyclohexylcarbamoyl,N-propyl-N-hexylcarbamoyl, etc.), di(C₃ -C₇)cycloalkylcarbamoyl (e.g.dicyclopropylcarbamoyl, dicyclopentylcarbamoyl, dicyclohexylcarbamoyl,etc.), N-[di(lower)alkylcarbamoyl(C₃ -C₇)cycloalkyl]carbamoyl [e.g.N-(1-(or 4-)dimethylcarbamoylcyclohexyl)carbamoyl, etc.],N-[di(lower)alkylcarbamoyl(lower)alkyl(C₃ -C₇)cycloalkyl]carbamoyl [e.g.N-[1-(or 4-)(dimethylcarbamoylmethyl)cyclohexyl]carbamoyl, etc.],N-[carbamoyl(lower)alkyl]carbamoyl [e.g.N-[1-carbamoyl-2-methylbutyl]carbamoyl, etc.],N-[N-(lower)alkylcarbamoyl(lower)alkyl]carbamoyl [e.g.N-(1-isopropylcarbamoyl-2-methylbutyl)carbamoyl, etc.], N-[N,N-loweralkylenecarbamoyl(lower)alkyl]carbamoyl [e.g.N-[2-methyl-1-(piperidinocarbonyl)butyl]carbamoyl, etc.],N-[N,N-di(lower)alkylcarbamoyl(lower)alkyl]carbamoyl [e.g.N-(dimethylcarbamoylmethyl)carbamoyl, N-[1-(or2-)(dimethylcarbamoyl)ethyl]carbamoyl,N-[1-(dimethylcarbamoyl)-2-methylpropyl]carbamoyl,N-[2,2-dimethyl-1-(dimethylcarbamoyl)propyl]carbamoyl,N-[2-methyl-1-(dimethylcarbamoyl)butyl]carbamoyl,N-[2-methyl-1-(diethylcarbamoyl)butyl]carbamoyl,N-[3-methyl-1-(dimethylcarbamoyl)butyl]carbamoyl,N-(1-dimethylcarbamoylpentyl)carbamoyl, etc.],N-(lower)alkyl-N-[N,N-di(lower)alkylcarbamoyl](lower)alkylcarbamoyl[e.g. N-methyl-N-[1-dimethylcarbamoyl- 2-methylbutyl]carbamoyl,N-methyl-N-[1-dimethylcarbamoyl-3-methylbutyl]carbamoyl, etc.],N-[N-(lower)cycloalkylcarbamoyl(lower)alkyl] carbamoyl [e.g.N-(1-cyclohexylcarbamoyl-2-methylbutyl)carbamoyl, etc.], and the like.

The aromatic acyl may include C₆ -C₁₀)aroyl (e.g. benzoyl, toluoyl,xyloyl, naphthoyl, etc.), (C₆ -C₁₀ )arenesulfonyl (e.g. benzenesulfonyl,tosyl, etc.), (C₆ -C₁₀)arylcarbamoyl (e.g. phenylcarbamoyl,tolylcarbamoyl, etc.), (C₆ -C₁₀)aryloxalyl (e.g. phenyloxalyl, etc.),and the like.

The heterocyclic acyl, wherein said heterocyclic group may be the sameas mentioned below, may include heterocyclecarbonyl (e.g. furoyl,thenoyl, 2-(or 3- or 4-)pyridylcarbonyl, thiazolylcarbonyl,thiadiazolylcarbonyl, tetrazolylcarbonyl, piperazinylcarbonyl,morpholinocarbonyl, thiomorpholinocarbonyl, indolylcarbonyl, etc.),lower or higher alkyleneaminocarbonyl (e.g. aziridin-1-ylcarbonyl,azetidn-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl,hexahydro-1H-azepin-1-ylcarbonyl, octahydroazocin-1-ylcarbonyl,tetrahydroquinolinecarbonyl, tetrahydroisoquinolinecarbonyl,dihydropyridinecarbonyl, tetrahydropyridinecarbonyl, etc.),heterocyclic-carbamoyl wherein said heterocyclic group may be the sameas mentioned below (e.g. pyridylcarbamoyl, piperidylcarbamoyl,hexahydro-1H-azepinylcarbamoyl, etc.), and the like.

The aliphatic acyl substituted with aromatic group(s) may include C₆-C₁₀)ar(lower)alkanoyl such as phenyl(lower)alkanoyl (e.g. phenylacetyl,phenylpropionyl, phenylhexanoyl, naphthylacetyl etc.), (C₆-C₁₀)ar(lower)alkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g.benzyloxycarbonyl, phenethyloxycarbonyl, etc.), phenoxy(lower)alkanoyl(e.g. phenoxyacetyl, phenoxypropionyl, etc.), (C₆-C₁₀)ar(lower)alkoxalyl such as phenyl(lower)alkoxalyl(e.g. benzyloxalyletc.), (C₆ -C₁₀)ar(lower)alkenoyl such as phenyl(lower)alkenoyl (e.g.cinnamoyl, etc.), (C₆ -C₁₀)ar(lower)alkylsulfonyl (e.g. benzylsulfonyl,etc.), and the like.

The aliphatic acyl substituted with heterocyclic group(s) may includeheterocyclic(lower)alkanoyl, wherein said heterocyclic group may be thesame as mentioned below (e.g. thienylacetyl, imidazolylacetyl,furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl,thienylpropionyl, thiadiazolylpropionyl, pyridylacetyl, etc.),heterocyclic-lower alkylcarbamoyl, wherein said heterocyclic group maybe the same as mentioned below (e.g. pyridylmethylcarbamoyl,morpholinoethylcarbamoyl, etc.), and the like.

These acyl groups may be further substituted with one or more,preferably one to three suitable substituent(s) such as hydroxy, loweralkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl,hexyl, etc.), halogen (e.g. chlorine, bromine, iodine, fluorine),carbamoyl, oxo, di(lower)alkylcarbamoyl, amino, protected amino such aslower alkanoylamino (e.g. formamido, acetamido, propionamido, etc.),lower alkoxycarbonylamino (e.g. t-butoxycarbonylamino, etc.), loweralkylsulfonyl (e.g. methylsulfonyl, etc.), arylsulfonyl (e.g.phenylsulfonyl, tosyl, etc.), ar(lower)alkyl (e.g. benzyl, etc.), loweralkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,etc.), carboxy, protected carboxy as mentioned below,carboxy(lower)alkyl (e.g. carboxymethyl, carboxyethyl, etc.), protectedcarboxy(lower)alkyl (e.g. t-butoxycarbonylmethyl, etc.) and the like.

Suitable examples of the above acyl groups which is further substitutedwith one or more, preferably one to three suitable substituent(s) may behalophenyl(lower)alkanoyl (e.g., 2-chlorophenylacetyl, etc.),(aminophenyl)(lower)alkanoyl (e.g. 4-aminophenylacetyl, etc.), [(loweralkoxycarbonylamino)phenyl](lower)alkanoyl [e.g.4-(t-butoxycarbonylamino)phenylacetyl, etc.], amino(lower)alkanoyl (e.g.2-amino-3-methylpentanoyl, etc.), (loweralkoxycarbonylamino)(lower)alkanoyl [e.g.2-(t-butoxycarbonylamino)-3-methylpentanoyl, etc.), lower alkanoylsubstituted suitable substituent(s) such as phenyl, amino, loweralkoxycabonylamino, etc. [e.g. 2-amino-2-phenylacetyl,2-(t-butoxycarbonylamino)-2-phenylacetyl, etc.],di(lower)alkylpiperidinylcarbonyl [e.g. 2,6-(or3,5-)dimethylpyperidin-1-ylcarbonyl, etc.],di(lower)alkylcarbamoyl]piperidinylcarbonyl [e.g.2-(dimethylcarbamoyl)piperidin-1-ylcarbonyl, etc.],di(lower)alkylcarbamoyl]pyrrolidinylcarbonyl [e.g.2-(dimethylcarbamoyl)pyrrolidin-1-ylcarbonyl, etc.], piperazinylcarbonylsubstituted by suitable substituent(s) such as lower alkyl, oxo, etc.[e.g. 4-methyl-3-oxo-2-(1-methylpropyl)piperazin-1-ylcarbonyl, etc.],N-(lower)alkyl-N-[hydroxy(lower)alkyl]carbamoyl e.g.N-methyl-N-(2-hydroxyethyl)carbamoyl, etc.],N-[hydroxy(lower)alkyl]carbamoyl [e.g.N-{1-(hydroxymethyl)-3-methylbutyl}carbamoyl, etc.], N-[(C₃-C₇)cycloalkyl(lower)alkyl]carbamoyl [e.g.N-(cyclohexylmethyl)carbamoyl, etc.], N-[carboxy(lower)alkyl]carbamoyl[e.g. N-(1-carboxy-2-methylbutyl)carbamoyl, etc.],N-[(lower)alkoxycarbonyl(lower)alkyl]carbamoyl [e.g.N-(1-methoxycarbonyl-2-methylbutyl)carbamoyl, etc.],(oxoheterocyclic)carbamoyl wherein said heterocyclic group may be thesame as mentioned below such as {oxo(hexahydro- 1H-azepinyl)}carbamoyl(e.g. ε-caprolactam-3-yl, etc.), etc.,N-[N-(lower)alkoxycarbonylpiperidinyl]carbamoyl [e.g.N-(N-ethoxycarbonylpiperidin-4-yl)carbamoyl, etc.],N-[N,N-di(lower)alkylcarbamoyl(lower)alkyl]carbamoyl substituted byphenyl or cyclo(lower)alkyl [e.g.N-{1-(N,N-dimethylcarbamoyl)-1-phenylmethyl}carbamoyl,N-{1-(N,N-dimethylcarbamoyl)-1-cyclohexylmethyl}carbamoyl, etc.],N-[hydroxy(C₃ -C₇)cycloalkyl]carbamoyl [e.g.N-(4-hydroxycyclohexyl)carbamoyl, etc.], N-(lower)alkoxyphenylcarbamoyl[e.g. N-(4-methoxyphenyl)carbamoyl, etc.], N-(loweralkanoylamino)carbamoyl [e.g. N-(2-methylpropanoylamino)carbamoyl,etc.], and the like.

Preferable example of acyl may be carbamoyl, lower alkanoyl (e.g.formyl, acetyl, propionyl, butyryl, isobutyryl, 3,3-dimethylbutyryl,4,4-dimethylvaleryl, valeryl, isovaleryl, pivaloyl, hexanoyl,3-methylvaleryl, etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl,etc.), lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.),(C₃ -C₇)cycloalkanecarbonyl (e.g. cyclohexanecarbonyl, etc.), (C₃-C₇)cycloalkyl(lower)alkanoyl (e.g. cyclohexylacetyl, etc.), C₃ -C₇cycloalkyloxycarbonyl (e.g. cyclohexyloxycarbonyl, etc.),morpholinocarbonyl(lower)alkanoyl (e.g. 3-morpholinocarbonylpropanoyl,etc.), lower or higher alkylcarbamoyl (e.g. methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,2-methylbutylcarbamoyl, pentylcarbamoyl, 1,3-dimethylbutylcarbamoylhexylcarbamoyl, hepthylcarbamoyl, octylcarbamoyl, nonylcarbamoyl, etc.),di(lower)alkylcarbamoyl (e.g. N-methyl-N-ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl,diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl,dihexylcarbamoyl, etc.), C₃ -C₇ cycloalkylcarbamoyl (e.g.cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl,cyclohexylcarbamoyl, cycloheptylcarbamoyl, etc.), N-lower alkyl-N-(C₃-C₇)cycloalkylcarbamoyl (e.g. N-methyl-N-cyclopropylcarbamoyl,N-methyl-N-cyclohexylcarbamoyl, N-ethyl-N-cyclohexylcarbamoyl,N-propyl-N-cyclohexylcarbamoyl, etc.), di(C₃ -C₇)cycloalklcarbamoyl(e.g. dicyclopropylcarbamoyl, dicyclopentylcarbamoyl,dicyclohexylcarbamoyl, etc.), N-[di(lower)alkylcarbamoyl(C₃ -C₇)cycloalkyl]carbamoyl [e.g. N-(1-(or4-)dimethylcarbamoylcyclohexyl)carbamoyl, etc.],N-[di(lower)alkylcarbamoyl(lower)alkyl(C₃ -C₇)cycloalkyl]carbamoyl [e.g.N-[1-(or 4-)(dimethylcarbamoylmethyl)cyclohexyl]carbamoyl, etc.],N-[carbamoyl(lower)alkyl]carbamoyl [e.g.N-[1-carbamoyl-2-methylbutyl]carbamoyl, etc.],N-[N-(lower)alkylcarbamoyl(lower)alkyl]carbamoyl [e.g.N-(1-isopropylcarbamoyl-2-methylbutyl)carbamoyl, etc.], N-[N,N-loweralkylenecarbamoyl(lower)alkyl]carbamoyl [e.g.N-[2-methyl-1-(piperidinocarbonyl)butyl]carbamoyl, etc.],N-[N,N-di(lower)alkylcarbamoyl(lower)alkyl]carbamoyl [e.g.N-(dimethylcarbamoylmethyl)carbamoyl, N-[1-(or2-)(dimethylcarbamoyl)ethyl)carbamoyl,N-[1-(dimethylcarbamoyl)-2-methylpropyl]carbamoyl,N-[2,2-dimethyl-1-(dimethylcarbamoyl)propyl]carbamoyl,N-[2-methyl-1-(dimethylcarbamoyl)butyl]carbamoyl,N-[2-methyl-1-(diethylcarbamoyl)butyl]carbamoyl,N-[3-methyl-1-(dimethylcarbamoyl)butyl]carbamoyl,N-(1-dimethylcarbamoylpentyl)carbamoyl, etc.],N-(lower)alkyl-N-[N,N-di(lower)alkylcarbamoyl](lower)alkylcarbamoyl[e.g. N-methyl-N-[1-dimethylcarbamoyl-2-methylbutyl]carbamoyl,N-methyl-N-[1-dimethylcarbamoyl-3-methylbutyl] carbamoyl, etc.],N-[N-(lower)cycloalkylcarbamoyl(lower)alkyl]carbamoyl [e.g.N-(1-cyclohexylcarbamoyl- 2-methylbutyl)carbamoyl, etc.], (C₆ -C₁₀)aroyl(e.g. benzoyl, toluoyl, xyloyl, naphthoyl, etc.), C₆ -C₁₀)arylcarbamoyl(e.g. phenylcarbamoyl, tolylcarbamoyl, etc.), (C₆ -C₁₀)aryloxalyl (e.g.phenyloxalyl, etc.), furoyl, thenoyl, 2-(or 3- or 4-)pyridylcarbonyl,thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl,piperazinylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl,indolylcarbonyl, lower alkyleneaminocarbonyl (e.g.aziridin-1-ylcarbonyl, azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl,piperidin-1-ylcarbonyl, hexahydro-1H-azepin-1-ylcarbonyl,octahydroazocin-1-ylcarbonyl, tetrahydroquinolinecarbonyl,tetrahydroisoquinolinecarbonyl, dihydropyridinecarbonyl,tetrahydropyridinecarbonyl, etc.), pyridylcarbamoyl, piperidylcarbamoyl,hexahydro-1H-azepinylcarbamoyl, (C₆ -C₁₀)ar(lower)alkanoyl such asphenyl(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl,phenylhexanoyl, naphthylacetyl, etc.), (C₆ -C₁₀)ar(lower)alkoxycarbonylsuch as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl,phenethyloxycarbonyl, etc.), (C₆ -C₁₀)ar(lower)alkoxalyl such asphenyl(lower)alkoxalyl (e.g. benzyloxalyl etc.), (C₆-C₁₀)ar(lower)alkenoyl such as phenyl(lower)alkenoyl (e.g. cinnamoyl,etc.), (C₆ -C₁₀)ar(lower)alkylsulfonyl (e.g. benzylsulfonyl, etc.),thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl,thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl,thiadiazolylpropionyl, pyridylacetyl, pyridylmethylcarbamoyl,morpholinoethylcarbamoyl, halophenyl(lower)alkanoyl (e.g.2-chlorophenylacetyl, etc.), (aminophenyl)(lower)alkanoyl (e.g.4-aminophenylacetyl, etc.), [(loweralkoxycarbonylamino)phenyl](lower)alkanoyl [e.g.4-(t-butoxycarbonylamino)phenylacetyl, etc.], amino(lower)alkanoyl (e.g.2-amino-3-methylpentanoyl, etc.), (loweralkoxycarbonylamino)(lower)alkanoyl [e.g.2-(t-butoxycarbonylamino)-3-methylpentanoyl, etc.], lower alkanoylsubstituted by suitable substituent(s) such as phenyl, amino, loweralkoxycarbonylamino [e.g. 2-amino-2-phenylacetyl,2-(t-butoxycarbonylamino)-2-phenylacetyl, etc.], etc.,di(lower)alkylpiperidinylcarbonyl [e.g. 2,6-(or3,5-)dimethylpiperidin-1-ylcarbonyl, etc.],[di(lower)alkylcarbamoyl]piperidinylcarbonyl [e.g.4-(dimethylcarbamoyl)piperidin-1-ylcarbonyl, etc.],[di(lower)alkylcarbamoyl]pyrrolidinylcarbonyl [e.g.2-(dimethylcarbamoyl)pyrrolidin-1-ylcarbonyl, etc.], piperazinylcarbonylsubstituted by suitable substituent(s) such as lower alkyl, oxo, etc.[e.g. 4-methyl-3-oxo-2-(1-methylpropyl)piperazin-1-ylcarbonyl, etc.],N-(lower)alkyl-N-[hydroxy(lower)alkyl]carbamoyl [e.g.N-methyl-N-(2-hydroxyethyl)carbamoyl, etc.],N-[hydroxy(lower)alkyl]carbamoyl [e.g.N-{1-(hydroxymethyl)-3-methylbutyl}carbamoyl, etc.], N-[(C₃-C₇)cycloalkyl(lower) alkyl]carbamoyl [e.g.N-(cyclohexylmethyl)carbamoyl, etc.], N-[carboxy(lower)alkyl]carbamoyl[e.g. N-(1-carboxy-2-methylbutyl)carbamoyl, etc.],N-[(lower)alkoxycarbonyl(loweralkyl]carbamoyl [e.g.N-(1-methoxycarbonyl-2-methylbutyl)carbamoyl, etc.],(oxoheterocyclic)carbamoyl such as {oxo(hexahydro-1H-azepinyl)}carbamoyl(e.g. ε-caprolactam-3-yl, etc.), etc.,N-[N-(lower)alkoxycarbonylpiperidinyl]carbamoyl [e.g.N-(N-ethoxycarbonylpiperidin-4-yl)carbamoyl, etc.],N-(N,N-di(lower)alkylcarbamoyl(lower)alkyl]carbamoyl substituted byphenyl or cyclo(lower)alkyl [e.g. N-{1-(N,N-dimethylcarbamoyl)-1-phenylmethyl}carbamoyl,N-{1-(N,N-dimethylcarbamoyl)-1-cyclohexylmethyl}carbamoyl, etc.],N-[hydroxy(C₃ -C₇)cycloalkyl]carbamoyl [e.g.N-(4-hydroxycyclohexyl)carbamoyl, etc.], N-(lower)alkoxyphenyl)carbamoyl[e.g. N-(4-methoxyphenyl)carbamoyl, etc.]N-(loweralkanoylamino)carbamoyl [e.g. N-(2-methylpropanoylamino)carbamoyl,etc.], and the like.

Suitable "lower alkyl" may include a straight or branched one such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,hexyl, and the like, in which the most preferred example may beisobutyl, 1-methylpropyl, n-butyl and 2,2-dimethylpropyl for R², andmethyl for R⁷.

Suitable "lower alkylene" may include a straight or branched one such asmethylene, ethylene, propylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, and the like, in which the most preferredexample may be methylene.

Suitable "protected carboxy" may include esterified carboxy and andamidated carboxy as mentioned above.

"Esterified carboxy" can be referred to the ones as mentioned below.

Suitable examples of the ester moiety of an esterified carboxy may bethe ones such as lower alkyl ester (e.g. methyl ester, ethyl ester,propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butylester, pentyl ester, hexyl ester, etc.) which may have at least onesuitable substituent(s) for example, lower alkanoyloxy(lower)alkyl ester[e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethylester, valeryloxymethyl ester, pivaloyloxymethyl ester,hexanolyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or3-)acetoxypropyl ester, 1-(or 2- or 3- or 4-)acetoxybutyl ester, 1-(or2-)propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester,1-(or 2-)butyryloxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, 1-(or2-)pivaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl ester,isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester,3,3-dimethylbutyryloxymethyl ester, 1-(or 2-)pentanoyloxyethyl ester,etc.], aroyl(lower)alkyl ester such as benzoyl(lower)alkyl ester (e.g.phenacyl ester, etc.), lower alkanesulfonyl(lower)alkyl ester (e.g.2-mesylethyl ester, etc.) mono(or di or tri)halo(lower)alkyl ester (e.g.2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); loweralkoxycarbonyloxy(lower)alkyl ester [e.g. methoxycarbonyloxymethylester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester,t-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester,1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or2-)isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene(lower)alkylester, or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester(e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynylester, propynyl ester, etc.); ar(lower)alkyl ester which may have atleast one suitable substituent(s) (e.g. benzyl ester, 4-methoxybenzylester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydrylester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); aryl ester which may haveat least one suitable substituent(s) (e.g. phenyl ester, 4-chlorophenylester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester,cumenyl ester, etc.); phthalidyl ester; and the like.

Preferable examples of the esterified carboxy thus defined may be loweralkoxycarbonyl, phenyl(lower)alkoxycarbonyl andbenzoyl(lower)alkoxycarbonyl, and the most preferable one may bemethoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl andphenacyloxycarbonyl.

Suitable "carboxy(lower)alkyl" means aforementioned lower alkyl which issubstituted by carboxy, wherein the preferable examples may becarboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl for R⁵.

Suitable "protected carboxy(lower)alkyl" means aforementioned loweralkyl which is substituted by above-mentioned "protected carboxy",wherein more preferable example may be lower alkoxycarbonyl(lower)alkyl,phenyl(lower)alkoxycarbonyl(lower)alkyl andbenzoyl(lower)alkoxycarbonyl(lower)alyl, and the most preferable one maybe methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl,methoxycarbonylbutyl, phenacyloxycarbonylmethyl,phenacyloxycarbonylethyl, phenacyloxycarbonylpropyl andphenacyloxycarbonylbutyl for R⁵.

Said "amidated carboxy" can be referred to the ones as mentioned below.

Suitable examples of the amidated carboxy may include

carbamoyl,

mono(or di)(lower)alkylcarbamoyl wherein the lower alkyl group may bethe same as those mentioned above (e.g. methylcarbamoyl, ethylcarbamoyl,isopropylcarbamoyl, butylcarbamoyl, 3-methylbutylcarbamoyl,isobutylcarbamoyl, pentylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl,etc.),

and further said lower alkyl may be substituted by the group consistingof

carboxy;

protected carboxy as mentioned above such as lower alkoxycarbonyl (e.g.methoxycarbonyl, ethoxycarbonyl, etc.), ar(lower)alkoxycarbonyl,preferably phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.),aroyl(lower)alkoxycarbonyl, preferably benzoyl(lower)alkoxycarbonyl(e.g. phenacyloxycarbonyl, etc.);

aryl (e.g. phenyl, naphthyl, etc.);

heterocyclic group as mentioned below such as saturated or unsaturated 5or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s)(e.g. pyridyl, pyrrolidinyl, etc.),

wherein said heterocyclic group may be further substituted by suitablesubstituent(s) such as oxo, carboxy, protected carboxy as mentionedabove and carbamoyl, for example, oxopyrrolidinyl substituted bycarboxy, lower alkoxycarbonyl or carbamoyl [e.g.2-oxo-5-carboxypyrrolidinyl, 2-oxo-5-ethoxycarbonylpyrrolidinyl,2-oxo-5-carbamoylpyrrolidinyl, etc.);

C₃ -C₇ cycloalkyl optionally substituted by carboxy or protected carboxyas mentioned above such as lower alkoxycarbonyl (e.g. carboxycyclohexyl,ethoxycarbonylcyclohexyl, etc.);

(C₃ -C₇ cycloalkylcarbamoyl (e.g. cyclohexylcarbamoyl, etc.),

carbamoyl substituted by amino or di(lower)alkylamino [e.g.N-aminocarbamoyl, N-(dimethylamino)carbamoyl, etc.],

N-(optionally substituted heterocyclic)carbamoyl wherein theheterocyclic moiety is the same as those mentioned above such as

saturated 5 or 6-membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s),

unsaturated 5 or 6-membered heteromonocyclic group

containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s),

unsaturated condensed 7 to 12-membered heterocyclic group containing 1to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s),

each of said heterocyclic group may be substituted by suitablesubstituent(s) such as hydroxy, protected hydroxy, halogen, loweralkoxy, lower alkyl, amino, nitro and cyano, for example,thiazolylcarbamoyl, benzothiazolylcarbamoyl, morpholinocarbamoyl,N-(lower alkylthiadiazoly)carbamoyl (e.g. methylthiadiazolylcarbamoyl,etc.),

lower alkyleneaminocarbonyl (e.g. pyrrolidin-1-ylcarbonyl,hexahydro-1H-azepin-1-ylcarbonyl, etc.),

said alkylene being optionally substituted by carboxy or protectedcarboxy as mentioned above such as lower alkoxycarbonyl [e.g.carboxypyrrolidin-1-ylcarbonyl,(methoxycarbonyl)pyrrolidin-1-ylcarbonyl,(ethoxycarbonyl)pyrrolidin-1-ylcarbonyl, etc.],

or said lower alkylene being optionally interrupted by other heteroatom(s) such as nitrogen, oxygen or sulfur (e.g. morpholinocarbonyl,etc.),

lower alkylsufonylcarbamoyl (e.g. methylsufonylcarbamoyl, etc.),

arenesulfonylcarbamoyl (e.g. benzenesulfonylcarbamoyl, etc.), and thelike.

Preferable example of the amidated carboxy thus defined may be:

carbamoyl,

mono(or di)lower alkyl carbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl,isopropylcarbamoyl, butylcarbamoyl, 3-methylbutylcarbamoyl,isobutylcarbamoyl, pentylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl,etc.),

N-(lower)alkyl-N-[carboxy(lower)alkyl]carbamoyl [e.g.N-methyl-N-(carboxymethyl)carbamoyl, etc.]

N-(lower)alkyl-N-[protected carboxy(lower)alkyl]carbamoyl such asN-(lower)alkyl-N-[lower alkoxycarbonyl(lower)alkyl]alkyl]carbamoyl [e.g.N-methyl-N-(methoxycarbonylmethyl)carbamoyl, etc.],

N-[carboxy(lower)alkyl]carbamoyl [e.g. N-(carboxymethyl)carbamoyl,N-(2-carboxyethyl)carbamoyl, N-(3-carboxypropyl)carbamoyl,N-(4-carboxybutyl)carbamoyl, N-(5-carboxypentyl)carbamoyl,N-(1-carboxyethyl)carbamoyl, N-(1-carboxy-2-methylpropyl)carbamoyl,N-(1-carboxy-3-methylbutyl)carbamoyl, 1,2-dicarboxyethyl)carbamoyl,etc.],

N-[protected carboxy(lower)alkyl]carbamoyl such as N-[loweralkoxycarbonyl(lower)alkyl]carbamoyl [e.g.N-(methoxycarbonylmethyl)carbamoyl, N-(2-methoxycarbonylethyl)carbamoyl,N-(3-methoxycarbonylpropyl)carbamoyl,N-(4-methoxycarbonylbutyl)carbamoyl,N-(5-methoxycarbonylpentyl)carbamoyl,N-[1,2-bis(methoxycarbonyl)ethyl]carbamoyl, etc.),

N-[ar(lower)alkoxycarbonyl(lower)alkyl]carbamoyl, preferablyN-[phenyl(lower)alkoxycarbonyl(lower)alkyl]carbamoyl [e.g.N-(benzyloxycarbonylmethyl)carbamoyl,N-(2-benzyloxycarbonylethyl)carbamoyl,N-(3-benzyloxycarbonylpropyl)carbamoyl,N-(4-benzyloxycarbonylbutyl)carbamoyl,N-(5-benzyloxycarbonylpentyl)carbamoyl, etc.),

N-[{aroyl(lower)alkoxy}(lower)alkyl]carbamoyl, preferablybenzoyl(lower)alkoxy(lower)alkyl]carbamoyl [e.g.N-(phenacyloxycarbonylmethyl)carbamoyl,N-(2-phenacyloxycarbonylethyl)carbamoyl,N-(3-phenacyloxycarbonylpropyl)carbamoyl,N-(4-phenacyloxycarbonylbutyl)carbamoyl,N-(5-phenacyloxycarbonylpentyl)carbamoyl,N-(1-phenacyloxyethyl)carbamoyl,N-(1-phenacyloxy-2-methylpropyl)carbamoyl,N-(1-phenacyloxy-3-methylbutyl)carbamoyl, etc.],

N-[carboxy(lower)alkyl]carbamoyl substituted by aryl such asN-[carboxy(lower)alkyl]carbamoyl substituted by phenyl or naphthyl [e.g.N-(1-carboxy-2-phenylethyl)carbamoyl, etc.],

N-[protected carboxy(lower)alkyl]carbamoyl substituted by aryl such asN-[{lower alkoxycarbonyl}(lower)alkyl]carbamoyl substituted by phenyl onnaphthyl [e.g. N-(1-ethoxycarbonyl-2-phenylethyl)carbamoyl, etc.],

N-[carboxy(lower)alkyl]carbamoyl substituted by heterocyclic group suchas pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and itsN-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl tetrazolyl anddihydrotriazinyl [e.g. N-{1-carboxy-2-(pyridin-2-yl)ethyl}carbamoyl,etc.],

N-[protected carboxy(lower)alkyl]carbamoyl substituted by heterocyclicgroup such as N-[lower alkoxycarbonyl(lower)alkyl]carbamoyl substitutedby pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and itsN-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl ordihydrotriazinyl [e.g. N-{1-ethoxycarbonyl-2-(pyridin-2-yl)ethyl}carbamoyl, etc.],

N-[aryl(lower)alkyl]carbamoyl such as phenyl(lower)alkylcarbamoyl (e.g.N-benzylcarbamoyl, etc.),

N-[{carboxy(C₃ -C₇)cycloalkyl}(lower)alkyl]carbamoyl [e.g.N-(4-carboxycyclohexylmethyl)carbamoyl, etc.],

N-[{protected carboxy(C₃ -C₇)cycloalkyl}(lower)alkyl]carbamoyl such asN-[{lower alkoxycarbonyl(C₃ -C₇)cycloalkyl}(lower)alkyl]carbamoyl [e.g.N-(4-ethoxycarbonylcyclohexylmethyl)carbamoyl, etc.],

N-[heterocyclic-(lower)alkyl]carbamoyl, said heterocyclic group beingazetidinyl, pyrrolidinyl, imidazolidinyl, peperidinyl, pyrazolidinyl andpeperazinyl, such as N-[pyrrolidinyl(lower)alkyl]carbamoyl [e.g.N-{2-(pyrrolidin-1-yl)ethyl}carbamoyl, etc.],

wherein said heterocyclic group may be substituted by suitablesubstituent(s) such as oxo, carboxy, protected carboxy as mentionedabove and carbamoyl, for example, oxopyrrolidinyl substituted bycarboxy, lower alkoxycarbonyl or carbamoyl [e.g.2-oxo-5-carboxypyrrolidinyl, 2-oxo-5-ethoxycarbonylpyrrolidinyl,2-oxo-5-carbamoylpyrrolidinyl, etc.);

(C₃ -C₇)cycloalkylcarbamoyl (e.g. cyclohexylcarbamoyl, etc.),

carbamoyl substituted by amino or di(lower)alkylamino [e.g.N-aminocarbamoyl, N-(dimethylamino)carbamoyl, etc.],

N-(optionally substituted heterocyclic)carbamoyl wherein theheterocyclic moiety being thiazolyl, 1,2-thiazolyl, thiazolinyl,thiadiazolyl, thiazolidinyl, benzothiazolyl, benzothiadiazolyl,morpholinyl, [e.g. thiazolylcarbamoyl, benzothiazolylcarbamoyl andmorpholinylcarbamoyl, etc.],

each of said heterocyclic group may be substituted by lower alkyl, forexample, N-(lower alkylthiadiazolyl)carbamoyl (e.g.methylthiadiazolylcarbamoyl, etc.),

lower alkyleneaminocarbonyl (e.g. pyrrolidin-1-ylcarbonyl,hexahydro-1H-azepin-1-ylcarbonyl, etc.),

lower alkyleneaminocarbonyl substituted by carboxy or protected carboxysuch as lower alkoxycarbonyl [e.g. 2-carboxypyrrolidin-1-ylcarbonyl,2-(methoxycarbonyl)pyrrolidin-1-ylcarbonyl,2-(ethoxycarbonyl)pyrrolidin-1-ylcarbonyl, etc.],

lower alkyleneaminocarbonyl wherein said lower alkylene beinginterrupted by oxygen (e.g. morpholinocarbonyl, etc.),

lower alkylsufonylcarbamoyl (e.g. methylsufonylcarbamoyl, etc.),

C₆ -C₁₀ arenesulfonylcarbamoyl (e.g. benzenesulfonylcarbamoyl, etc.),and the like.

Suitable "optionally substituted heterocyclic(lower)alkyl" meansaforementioned lower alkyl, which is substituted by saturated orunsaturated, monocyclic or polycyclic heterocyclic group containing atleast one hetero-atom such as an oxygen, sulfur, nitrogen atom and thelike.

More preferable heterocyclic moiety may be heterocyclic group such as:

unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclicgroup containing 1 to 4 nitrogen atom(s), for example, pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.,1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g.,4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;

saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclicgroup containing 1 to 4 nitrogen atom(s), for example, azetidinyl,pyrrolidinyl, imidazolidinyl, piperidinyl, pyrazolidinyl, piperazinyl,etc;

unsaturated condensed 7 to 12-membered heterocyclic group containing 1to 5 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc.;

unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), forexample, oxazolyl, isoxazolyl, oxadiazolyl, (e.g., 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;

saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), forexample, morpholinyl, etc.;

unsaturated condensed 7 to 12-membered heterocyclic group containing 1to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,benzoxazolyl, benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclicgroup containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), forexample, thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,2,3-thiadiazolyl), etc.;

saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclicgroup containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), forexample, thiazolidinyl, etc.;

unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclicgroup containing a sulfur atom, for example, thienyl, etc.;

unsaturated condensed 7 to 12-membered heterocyclic group containing 1to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,benzothiazolyl, benzothiadiazolyl, etc. and the like;

wherein said heterocyclic group may be substituted by one or more,preferably one or two suitable substituents) such as:

hydroxy;

protected hydroxy, in which the hydroxy group is protected by aconventional hydroxy-protective group such as acyl as mentioned above,tri(lower)alkylsilyl (e.g. t-butyldimethylsilyl, etc.), etc.;

halogen (e.g. chlorine, bromine, iodine or fluorine);

lower alkoxy, which may be straight or branched one alkoxy such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.,more preferably C₁ -C₄ alkoxy (e.g. methoxy, etc.);

lower alkyl as mentioned above, more preferably C₁ -C₄ alkyl (e.g.methyl, etc.); amino; nitro; cyano; and the like.

And further when said heterocyclic group has imino-moiety(ies) in itsring, the imino-moiety(ies) may be substituted by suitablesubstituent(s) such as;

lower alkyl as mentioned above (e.g. methyl, ethyl, propyl, isobutyl,etc.);

imino-protective group as mentioned below, more preferably loweralkanoyl (e.g. formyl, etc.), arenesulfonyl (e.g. tosyl, etc.); and thelike.

Preferable example of "optionally substituted heterocyclic(lower)alkyl "thus defined may be:

lower alkyl substituted by unsaturated 5 or 6-membered heteromonocyclicgroup containing 1 to 4 nitrogen atom(s), such as pyridyl(lower)alkyl,imidazolyl(lower)alkyl, etc.;

lower alkyl substituted by unsaturated condensed 7 to 12-memberedheterocyclic group containing 1 to 5 nitrogen atom(s), such asindolyl(lower)alkyl, etc.;

lower alkyl substituted by unsaturated 5 or 6-membered heteromonocyclicgroup containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) suchas thiazolyl(lower)alkyl, etc.; and the like,

wherein said heterocyclic group may be substituted by suitablesubstituent(s) such as lower alkyl (e.g. methyl, ethyl propyl, isobutyl,etc.), lower alkanoyl (e.g. formyl, etc.), (C₆ -C₁₀)arenesulfonyl (e.g.tosyl, etc.), and the like.

More preferable example may be :

pyridyl(lower)alkyl [e.g. 2-(or 3- or 4-)pyridylmethyl, etc.],

imidazolyl(lower)alkyl [e.g. imidazol-1(or 3)-yl methyl, etc.],

indolyl(lower)alkyl [e.g. indol-3-ylmethyl, etc.],

thiazolyl(lower)alkyl [e.g. thiazol-3-ylmethyl, etc.],

N-arenesulfonylimidazolyl(lower)alkyl (e.g. 1-tosylimidazol-3-ylmethyl,etc.),

N-(lower)alkanoylindolyl(lower)alkyl (e.g. N-formylindol-3-ylmethyl,etc.), and

N-(lower)alkylindoyl(lower)alkyl [e.g. N-methyl(or ethyl or propyl orisobutyl)indol-3-ylmethyl, etc.]for R³ ; and

pyridyl(lower)alkyl (e.g. 2-pyridylmethyl, etc.),

imidazolyl(lower)alkyl [e.g. imidazol-1(or 3)-ylmethyl, etc.], and

N-arenesulfonylimidazolyl(lower)alkyl (e.g. 1-tosylimidazol-3-ylmethyl,etc.) for R²,

and the most preferred one may be:

indolyl(lower)alkyl, N-(lower)alkanoylindolyl(lower)alkyl andN-(lower)alkylindolyl(lower)alkyl for R³, and

pyridyl(lower)alkyl and imidazolyl(lower)alkyl for R².

Suitable "ar(lower)alkyl" may include C₆ -C₁₀ ar(lower)alkyl such asphenyl(lower)alkyl (e.g. benzyl, phenethyl, etc.), tolyl(lower)alkyl,xylyl(lower)alkyl, naphthyl(lower)alkyl (e.g. naphthylmethyl, etc.), andthe like, wherein said ar(lower)alkyl may be substituted by suitablesubstituent(s) such as those mentioned in the explanation of "optionallysubstituted heterocyclic(lower)alkyl" as mentioned above.

Preferable example of optionally substituted ar(lower)alkyl may bephenyl(lower)alkyl and naphthyl(lower)alkyl, and the most preferable onemay be benzyl and naphthylmethyl for R², and benzyl for R³

Suitable "lower alkylimino" means imino group substituted byaforementioned lower alkyl, in which the most preferable example may bemethylimino.

Suitable "cyclo(lower)alkyl(lower)alkyl" means aforementioned loweralkyl which is substituted by C₃ -C₇ cyclo(lower)alkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike, wherein more preferable example may be C₄ -C₆cyclo(lower)alkyl(lower)alkyl and the most preferable one may becyclohexylmethyl.

Suitable "optionally substituted lower alkyl" may include aforementionedlower alkyl (e.g. methyl, ethyl, isopropyl, butyl, isobutyl, etc.) whichis optionally substituted by suitable substituent(s) such as optionallysubstituted heterocyclic group as mentioned above (e.g. pyridyl,thiazolyl, imidazolyl, N-tosylimidazolyl, etc.); C₆ -C₁₀ aryl asmentioned below (e.g. phenyl, naphthyl, etc.); amino; protected amino asmentioned below (e.g. benzyloxycarbonylamino, etc.); carboxy; protectedcarboxy as mentioned above (e.g. benzyloxycarbonyl, etc.); and the like.

Preferable example of "optionally substituted lower alkyl" thus definedmay be:

lower alkyl (e.g. isopropyl, isobutyl, etc.),

pyridyl(lower)alkyl [e.g. 2-(or 3- or 4-)pyridylmethyl,2-(2-pyridyl)ethyl, etc.],

thiazolyl(lower)alkyl [e.g. 3-thiazolylmethyl, etc.],

imidazolyl(lower)alkyl [e.g. 2-(or 3-)imidazolylmethyl, etc.],

N-protected imidazolyl(lower)alkyl such asN-(arenesulfonyl)imidazolyl(lower)alkyl [e.g. N-tosyl-2-(or3-)imidazolylmethyl, etc.],

C₆ -C₁₀ ar(lower)alkyl such as phenyl(lower)alkyl (e.g. benzyl,naphthylmethyl, etc.),

amino(lower)alkyl (e.g. 4-aminobutyl, etc.),

protected amino(lower)alkyl such as C₆ -C₁₀ ar(lower)alkoxycarbonyl[e.g. 4-(benzyloxycarbonylamino)butyl, etc.],

carboxy(lower)alkyl (e.g. carboxymethyl, 2-carboxyethyl, etc.),

protected carboxy(lower)alkyl such as C₆ -C₁₀ar(lower)alkoxycarbonyl(lower)alkyl (e.g. benzyloxycarbonylmethyl,2-benzyloxycarbonylethyl, etc.), and the like.

The most preferable example of "optionally substituted lower alkyl" thusdefined may be:

isopropyl, isobutyl,

2-(or 3- or 4-)pyridylmethyl, 2-(2-pyridyl)ethyl, 3-thiazolylmethyl,2-(or 3-)imidazolylmethyl,

N-tosyl-2-(or 3-)imidazolylmethyl,

benzyl, naphthylmethyl,

4-aminobutyl, 4-(benzyloxycarbonylamino)butyl,

carboxymethyl, 2-carboxyethyl,

benzyloxycarbonylmethyl and 2-benzyloxycarbonylethyl for R⁴ ; and

2-pyridylmethyl and 2-(2-pyridyl)ethyl for R⁶.

Suitable "optionally substituted heterocyclic group" may include thesame heterocyclic moiety as mentioned before such as pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidyl,pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g.4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.),thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,2,3-thiadiazolyl), and the like, wherein said heterocyclic group isoptionally substituted by the same substituent(s) mentioned therein suchas imino-protective group (e.g. arenesulfonyl, etc.).

Suitable "aryl[ may include C₆ -C₁₀ aryl such as phenyl, tolyl, xylyl,cumenyl, naphthyl, and the like, in which more preferable example may bephenyl and naphthyl.

Suitable amino- or imino-protective group for protected amino orprotected imino may include acyl as mentioned above, in which morepreferable example may be lower alkanoyl, (C₆-C₁₀)ar(lower)alkoxycarbonyl and (C₆ -C₁₀) arenesulfonyl, and the mostpreferable one may be benzyloxycarbonyl.

Suitable "imino containing heterocyclic(lower)alkyl optionallysubstituted by suitable substituent(s)" means those given for"optionally substituted heterocyclic(lower)alkyl" mentioned above, inwhich the heterocyclic ring contains an imino group (--NH--), such asindolyl(lower)alkyl, imidazolyl(lower)alkyl, and the like.

Suitable "protected imino containing heterocyclic(lower)alkyl optionallysubstituted by suitable substituent(s)" means aforementioned "iminocontaining heterocyclic(lower)alkyl optionally substituted by suitablesubstituent(s)", in which the imino group is protected by a conventionalimino-protective group as mentioned below.

"Acyl substituted by a protected amino group" means the acyl asexplained above which is substituted by the protected amino as mentionedabove.

"Acyl substituted by an amino group" means the acyl as explained abovewhich is substituted by amino group.

Suitable "imino-protective group" may include conventional ones used inthe peptide chemistry such as those given for the amino-protective groupin the protected amino.

The preferred embodiments of each definition may be as follows:

R¹ is acyl such as carbamoyl, or an organic carboxylic, an organiccarbonic, an organic sulfonic or an organic carbamic acyl, for instance:

lower alkanoyl (e.g. acetyl, propionyl, 3,3-dimethylbutyryl, pivaloyl,4-methylpentanoyl, etc.); amino(lower)alkanoyl (e.g.2-amino-3-methylpentanoyl, etc.);

protected amino(lower)alkanoyl, for example, acylamino(lower)alkanoylsuch as lower alkoxycarbonylamino(lower)alkanoyl (e.g.2-tert-butoxycarbonylamino-3-methylpentanoyl, etc.), C₃ -C₇cycloalkylureido(lower)alkanoyl (e.g.2-(3-cyclohexylureido)-3-methylpentanoyl, etc.);

lower alkoxycarbonyl (e.g. tert-butoxycarbonyl, etc.);

C₃ -C₇ cycloalkyl(lower)alkanoyl (e.g. cyclohexylacetyl, etc.);

C₃ -C₇ cycloalkylcarbonyl (e.g. cyclohexylcarbonyl, etc.);

C₃ -C₇ cycloalkyloxycarbonyl (e.g. cyclohexyloxycarbonyl, etc.);

aroyl such as C₆ -C₁₀ aroyl (e.g. benzoyl, 1- or 2-naphthoyl, etc.);

ar(lower)alkanoyl such as C₆ -C₁₀ ar(lower)alkanoyl (e.g. phenylacetyl,1- or 2-naphthylacetyl, 3-phenylpropionyl, etc.);

amino-substituted ar(lower)alkanoyl, for example, amino-substituted (C₆-C₁₀)ar(lower)alkanoyl such as amino-substituted phenyl(lower)alkanoyl(e.g. 2-amino-2-phenylacetyl, etc.);

protected amino-substituted ar(lower)alkanoyl, for example,acylamino-substituted (C₆ -C₁₀)ar(lower)alkanoyl such as loweralkoxycarbonylamino-substituted phenyl(lower)alkanoyl (e.g.2-(4-tert-butoxycarbonylaminophenyl)acetyl,2-tert-butoxycarbonylamino-2-phenylacetyl, etc.);

haloar(lower)alkanoyl, for example, halo(C₆ -C₁₀)ar(lower)alkanoyl suchas halophenyl(lower)alkanoyl (e.g. (2-chlorophenyl)acetyl, etc.);

ar(lower)alkenoyl, for example, C₆ -C₁₀ ar(lower)alkenoyl such asphenyl(lower)alkenoyl (e.g. cinnamoyl, etc.);

arylglyoxyloyl such as C₆ -C₁₀ arylglyoxyloyl (e.g. phenylglyoxyloyl,etc.);

ar(lower)alkylglyoxyloyl such as C₆ -C₁₀ ar(lower)alkylglyoxyloyl (e.g.benzylglyoxyloyl, etc.);

pyridylcarbonyl (e.g. 2- or 3- or 4-pyridylcarbonyl, etc.);

tetrahydropyridylcarbonyl (e.g.1,2,3,6-tetrahydropropyridin-1-ylcarbonyl, etc.);

tetrahydroquinolylcarbonyl (e.g.1,2,3,4-tetrahydroquinolin-1-ylcarbonyl, etc.);

tetrahydroisoquinolylcarbonyl (e.g.1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyl, etc.);

morpholinylcarbonyl (e.g. morpholinocarbonyl, etc.);

thiomorpholinylcarbonyl (e.g. thiomorpholinocarbonyl, etc.);

indolylcarbonyl (e.g. 2-indolylcarbonyl, etc.);

piperazinylcarbonyl substituted by one to three substituents selectedfrom oxo and lower alkyl (e.g.4-methyl-2-(1-methylpropyl)-3-oxopiperazin-1-yl-carbonyl, etc.);

pyridyl(lower)alkanoyl (e.g. 2- or 3- or 4-pyridylacetyl, etc.);

morpholinylcarbonyl(lower)alkanoyl (e.g.3-(morpholinocarbonyl)propionyl, etc.);

ar(lower)alkylsulfonyl, for example, C₆ -C₁₀ ar(lower)alkylsulfonyl suchas phenyl(lower)alkylsulfonyl (e.g. benzylsulfonyl, etc.);

N- or N,N-di(lower or higher)alkylcarbamoyl such as N- or N,N-di(C₁-C₁₀)alkylcarbamoyl (e.g. isopropylcarbamoyl, 2-methylbutylcarbamoyl,heptylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl,diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl, etc.);

hydroxy(lower)alkylcarbamoyl (e.g.1-hydroxymethyl-3-methylbutylcarbamoyl, etc.);

carboxy(lower)alkylcarbamoyl (e.g. 1-carboxy-2-methylbutylcarbamoyl,etc.);

protected carboxy(lower)alkylcarbamoyl, for example, esterifiedcarboxy(lower)alkylcarbamoyl such as loweralkoxycarbonyl(lower)alkylcarbamoyl (e.g.1-methoxycarbonyl-2-methylbutylcarbamoyl, etc.);

carbamoyl(lower)alkylcarbamoyl (e.g. 1-carbamoyl-2-methylbutylcarbamoyl,etc.);

[N- or N,N-di(lower)alkylcarbamoyl](lower)alkylcarbamoyl (e.g.1-isopropylcarbamoyl-2-methylbutylcarbamoyl,dimethylcarbamoylmethylcarbamoyl, 1-(dimethylcarbamoyl)ethylcarbamoyl,2-(dimethylcarbamoyl)ethylcarbamoyl,1-(dimethylcarbamoyl)-2-methylpropylcarbamoyl,1-(dimethylcarbamoyl)-2,2-dimethylpropylcarbamoyl,1-(dimethylcarbamoyl)-2-methylbutylcarbamoyl,1-(dimethylcarbamoyl)-3-methylbutylcarbamoyl,1-(diethylcarbamoyl)-2-methylbutylcarbamoyl,1-(dimethylcarbamoyl)pentylcarbamoyl, etc.);

N-lower alkyl-N-[hydroxy(lower)alkyl]carbamoyl (e.g.N-(2-hydroxyethyl)-N-methylcarbamoyl, etc.);

N-lower alkyl-N-[di(lower)alkylcarbamoyl(lower)alkyl]carbamoyl (e.g.N-(1-dimethylcarbamoyl-2-methylbutyl)-N-methylcarbamoyl,N-(1-dimethylcarbamoyl-3-methylbutyl)-N-methylcarbamoyl, etc.);

lower or higher alkyleneaminocarbonyl such as C₃ -C₁₀alkyleneaminocarbonyl (e.g. pyrrolidin-1-ylcarbonyl,piperidin-1-ylcarbonyl, 3,5- or 2,6-dimethylpiperidin-1-ylcarbonyl,hexahydro-1H-azepin-1-ylcarbonyl, octahydroazocin-1-ylcarbonyl, etc.);

di(lower)alkylcarbamoyl(lower)alkyleneaminocarbonyl (e.g.2-(dimethylcarbamoyl)pyrrolidin-1-ylcarbonyl,4-(dimethylcarbamoyl)piperidin-1-ylcarbonyl, etc.);

N-lower alkyl-N-(C₃ -C₇)cycloalkylcarbamoyl (e.g.N-cyclohexyl-N-methylcarbamoyl, etc.);

mono- or di(C₃ -C₇)cycloalkylcarbamoyl (e.g. cyclohexylcarbamoyl,dicyclohexylcarbamoyl, etc.);

hydroxy- or di(lower)alkylcarbamoyl- ordi(lower)alkylcarbamoyl(lower)alkyl-substituted (C₃-C₇)cycloalkylcarbamoyl (e.g. 4-hydroxycyclohexylcarbamoyl, 1- or4-(dimethylcarbamoyl)cyclohexylcarbamoyl, 1- or4-(dimethylcarbamoylmethyl)cyclohexylcarbamoyl, etc.);

C₃ -C₇ cycloalkyl(lower)alkylcarbamoyl (e.g. cyclohexylmethylcarbamoyl,etc.);

di(lower)alkylcarbamoyl-substituted C₃ -C₇cycloalkyl(lower)alkylcarbamoyl (e.g.[1-cyclohexyl-1-(dimethylcarbamoyl)methyl]carbamoyl, etc.);

di(lower)alkylcarbamoyl-substituted ar(lower)alkylcarbamoyl such asdi(lower)alkylcarbamoyl-substituted phenyl(lower)alkylcarbamoyl (e.g.[1-phenyl-1-(dimethylcarbamoyl)methyl]carbamoyl, etc.);

arylcarbamoyl, preferably C₆ -C₁₀ arylcarbamoyl, in which the aryl groupmay be substituted by one to three substituents selected from halogen,lower alkyl and lower alkoxy (e.g. phenylcarbamoyl, 2- or 3- or4-chlorophenylcarbamoyl, 4-tolylcarbamoyl, 4-methoxyphenylcarbamoyl,etc.);

pyridylcarbamoyl (e.g. 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, etc.);

N-protected piperidylcarbonyl, for example, N-acylpireridylcarbonyl suchas N-lower alkoxycarbonylpiperidylcarbonyl (e.g.1-ethoxycarbonylpiperidin-4-ylcarbonyl, etc.);

morpholinyl(lower)alkylcarbamoyl (e.g. 2-(morpholino)ethylcarbamoyl,etc.);

lower alkanoylcarbazoyl (e.g. 3-isobutyrylcarbazoyl, etc.);

lower alkyleneaminocarbamoyl (e.g. piperidin-1-ylcarbamoyl, etc.);

N-(C₃ -C₇)cycloalkylcarbamoyl(lower)alkylcarbamoyl (e.g.1-cyclohexylcarbamoyl-2-methylbutylcarbamoyl, etc.);

lower alkyleneaminocarbonyl(lower)alkylcarbamoyl (e.g.1-(piperidin-1-ylcarbonyl)-2-methylbutylcarbamoyl, etc.);

pyridyl(lower)alkylcarbamoyl (e.g. 2-pyridylmethylcarbamoyl, etc.); or

oxo-substituted hexahydroazepinylcarbamoyl (e.g.2-oxo-hexahydro-1H-azepin-3-ylcarbamoyl, etc.);

particularly,

N,N-di(lower)alkylcarbamoyl;

mono- or di(C₃ -C₇)cycloalkylcarbamoyl;

N-lower alkyl-N-(C₃ -C₇)cycloalkylcarbamoyl;

N-lower alkyl-N-[di(lower)alkylcarbamoyl(lower)alkyl]carbamoyl;

C₆ -C₁₀ arylcarbamoyl;

lower or higher alkyleneaminocarbonyl such as C₃ -C₁₀alkyleneaminocarbonyl; or

N-lower alkyl-N-[hydroxy(lower)alkyl]carbamoyl;

R² is lower alkyl (e.g. butyl, isobutyl, 1-methylpropyl,2,2-dimethylpropyl, etc.);

particularly, isobutyl;

R³ is indolyl(lower)alkyl (e.g. 3-indolylmethyl, etc.);

N-(lower)alkylindolyl(lower)alkyl (e.g. 1-methyl-3-indolylmethyl,1-ethyl-3-indolylmethyl, 1-propyl-3-indolylmethyl,1-isobutyl-3-indolylmethyl, etc.);

N-acylindolyl(lower)alkyl such as N-(lower) alkanoylindolyl(lower)alkyl(e.g. 1-formyl-3-indolylmethyl, etc.; or

ar(lower)alkyl such as C₆ -C₁₀ ar(lower)alkyl (e.g. benzyl, 1- or2-naphthylmethyl, etc.);

particularly,

N-(lower)alkylindolyl(lower)alkyl such as 1-methyl-3-indolylmethyl;

R⁴ is hydrogen,

lower alkyl (e.g. isopropyl, isobutyl, etc.);

amino(lower)alkyl (e.g. 4-aminobutyl, etc.);

protected amino(lower)alkyl, for example, acylamino(lower)alkyl such asmono- or di or triphenyl(lower)alkoxycarbonylamino(lower)alkyl (e.g.4-benzyloxycarbonylaminobutyl, etc.);

carboxy(lower)alkyl (e.g. carboxymethyl, 2-carboxyethyl, etc.);

protected carboxy(lower)alkyl, for example, esterifiedcarboxy(lower)alkyl such as mono- or di ortriphenyl(lower)alkoxycarbonyl(lower)alkyl (e.g.benzyloxycarbonylmethyl, 2-benzyloxycarbonylethyl, etc.);

ar(lower)alkyl such as C₆ -C₁₀ ar(lower)alkyl (e.g. benzyl, 1- or2-naphthylmethyl, etc.);

pyridyl(lower)alkyl (e.g. 2- or 3- or 4-pyridylmethyl, etc.);

imidazolyl(lower)alkyl (e.g. 1H-4-imidazolylmethyl, etc.); or

thiazolyl(lower)alkyl (e.g. 4-thiazolylmethyl, etc.);

particularly,

C₆ -C₁₀ ar(lower)alkyl such as benzyl; or

pyridyl(lower)alkyl such as 2-pyridylmethyl;

R⁵ is carboxy;

esterified carboxy such as:

lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.),

ar(lower)alkoxycarbonyl such as mono or di ortriphenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.),

aroyl(lower)alkoxycarbonyl such as benzoyl(lower)alkoxycarbonyl (e.g.phenacyl, etc.);

amidated carboxy such as: carbamoyl,

N- or N,N-di(lower)alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl,propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl etc.),

lower alkylcarbamoyl substituted by one or two substituents selectedfrom carboxy and protected carboxy (preferably, esterified carboxy, morepreferably, lower alkoxycarbonyl, mono or di ortriphenyl(lower)alkoxycarbonyl or benzoyl(lower)alkoxycarbonyl) (e.g.carboxymethylcarbamoyl, 1- or 2-carboxyethylcarbamoyl,4-carboxybutylcarbamol, 5-carboxypentylcarbamoyl,1-carboxy-2-methylpropylcarbamoyl, 1-carboxy-3-methylbutylcarbamoyl,1,2-dicarboxyethylcarbamoyl, benzyloxycarbonylmethylcarbamoyl,2-benzyloxycarbonylethylcarbamoyl, 1- or2-phenacyloxycarbonylethylcarbamoyl,4-phenacyloxycarbonylbutylcarbamoyl,5-phenacyloxycarbonylpentylcarbamoyl,1-methoxycarbonyl-2-methylpropylcarbamoyl,1-methoxycarbonyl-3-methylbutylcarbamoyl,1,2-bis(methoxycarbonyl)ethylcarbamoyl, etc.),

N-(lower)alkyl-N-[carboxy- or protected carboxy (preferably, esterifiedcarboxy, more preferably lower alkoxycarbonyl)(lower)alkyl]carbamoyl(e.g. N-methyl-N-(carboxymethyl)carbamoyl,N-methyl-N-(methoxycarbonylmethyl)carbamoyl, etc.),

ar(lower)alkylcarbamoyl, for example, C₆ -C₁₀ ar(lower)alkylcarbamoylsuch as phenyl(lower)alkylcarbamoyl (e.g. benzylcarbamoyl, etc.),

carboxy- or protected carboxy (preferably, esterifiedcarboxy)-substituted ar(lower)alkylcarbamoyl such as carboxy- or loweralkoxycarbonyl-substituted phenyl(lower)alkylcarbamoyl (e.g.1-carboxy-2-phenylethylcarbamoyl,1-ethoxycarbonyl-2-phenylethylcarbamoyl, etc.),

C₃ -C₇ cycloalkylcarbamoyl (e.g. cyclohexylcarbamoyl, etc.),

N-[carboxy- or protected carboxy-substituted C₃ -C₇cycloalkyl(lower)alkyl]carbamoyl, for example, [carboxy(C₃-C₇)cycloalkyl(lower)alkyl]carbamoyl (e.g.4-carboxycyclohexylmethylcarbamoyl, etc.), [esterifiedcarboxy-substituted C₃ -C₇ cycloalkyl(lower carbamoyl such as loweralkoxycarbonyl(C₃ -C₇)cycloalkyl(lower)alkyl]carbamoyl (e.g.4-(ethoxycarbonyl)cyclohexylmethylcarbamoyl, etc.),

acylcarbamoyl such as lower alkylsulfonylcarbamoyl (e.g.methylsulfonylcarbamoyl, etc.), arylsulfonylcarbamoyl, for example, C₆-C₁₀ arylsulfonylcarbamoyl (e.g. phenylsulfonylcarbamoyl, etc.),

carboxy- or protected carboxy (preferably, esterifiedcarboxy)-substituted pyridyl(lower)alkylcarbamoyl such as carboxy- orlower alkoxycarbonyl-substituted pyridyl(lower)alkylcarbamoyl (e.g.1-carboxy-2-(2-pyridyl)ethylcarbamoyl,1-ethoxycarbonyl-2-(2-pyridyl)ethylcarbamoyl, etc.)

lower alkyleneaminocarbonyl (e.g. pyrrolidin-1-ylcarbonyl,piperidin-1-ylcarbonyl, etc.), lower alkyleneaminocarbonyl substitutedby carboxy or protected carboxy (preferably, esterified carboxy, morepreferably, lower alkoxycarbonyl) (e.g.2-carboxypyrrolidin-1-ylcarbonyl,2-methoxycarbonylpyrrolidin-1-ylcarbonyl, etc.),

[lower alkyleneamino(lower)alkyl]carbamoyl substituted by one to twosubstituents selected from carboxy, protected carboxy (preferably,esterified carboxy, more preferably, lower alkoxycarbonyl) and carbamoyl(e.g. 2-(2-carboxy-5-oxopyrrolidin-1-yl)ethylcarbamoyl,2-(2-ethoxycarbonyl-5-oxopyrrolidin-1-yl)ethylcarbamoyl,2-(2-carbamoyl-5-oxopyrrolidin-1-yl)ethylcarbamoyl, etc.),

morpholinocarbonyl,

morpholinylcarbamoyl (e.g. morpholinocarbamoyl, etc.),

pyridylcarbamoyl (e.g. 2-pyridylcarbamoyl, etc.),

thiazolylcarbamoyl (e.g. 2-thiazolylcarbamoyl, etc.),

lower alkylthiadiazolylcarbamoyl such as5-(lower)alkyl-1,3,4-thiadiazolylcarbamoyl (e.g.5-methyl-1,3,4-thiadiazolylcarbamoyl, etc.),

benzothiazolylcarbamoyl (e.g. 2-benzothiazolyl

carbamoyl, etc.),

morpholinyl(lower)alkylcarbamoyl (e.g. 2-morpholino

ethylcarbamoyl, etc.),

pyridyl(lower)alkylcarbonyl (e.g. 2-pyridylmethylcarbonyl, etc.),

carbazoyl,

di(lower)alkylcarbazoyl (e.g. 3,3-dimethylcarbazoyl, etc.);

carboxy(lower)alkyl (e.g. carboxymethyl, 2-carboxyethyl,3-carboxypropyl, 4-carboxybutyl, etc.); or

protected carboxy(lower)alkyl, for example esterifiedcarboxy(lower)alkyl such as lower alkoxycarbonyl(lower)alkyl (e.g.methoxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl,4-methoxycarbonylbutyl, etc.), aroyl(lower)alkoxycarbonyl(lower)alkyl(e.g. phenacyloxycarbonylmethyl, 2-phenacyloxycarbonylethyl,3-phenacyloxycarbonylpropyl, 4-phenacyloxycarbonylbutyl, etc.);

particularly,

carboxy;

lower alkoxycarbonyl; or

carbamoyl;

N- or N,N-di(lower)alkylcarbamoyl;

R⁶ is hydrogen; or

pyridyl(lower)alkyl (e.g. 2-pyridylmethyl, 2-(2-pyridyl)ethyl, etc.);

particularly, hydrogen;

R⁷ is hydrogen; or

lower alkyl (e.g. methyl, etc.);

particularly, hydrogen; and

A is lower alkylene (e.g. methylene, etc.); --O--; --NH--; or

lower alkylimino (e.g. methylimino, etc.);

particularly, methylene or --NH--.

The processes for preparing the object compound (I) are explained indetail in the following.

PROCESS 1

The object compound (I) or a salt thereof can be prepared by reactingthe compound (II) or its reactive derivative at the carboxy group, or asalt thereof with the compound (III) or its reactive derivative at theamino group, or a salt thereof.

Suitable reactive derivative at the amino group of the compound (III)may include Schiff's base type imino or its tautomeric enamine typeisomer formed by the reaction of the compound (III) with a carbonylcompound such as aldehyde, ketone or the like; a silyl derivative formedby the reaction of the compound (III) with a silyl compound such asbis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,bis(trimethylsilyl)urea or the like; a derivative formed by reaction ofthe compound (III) with phosphorus trichloride or phosgene, and thelike.

Suitable salts of the compound (III) and its reactive derivative can bereferred to the acid addition salts as exemplified for the compound (I).

Suitable reactive derivative at the carboxy group of the compound (II)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. Suitable examples of the reactivederivatives may be an acid chloride; an acid azide; a mixed acidanhydride with acid such as substituted phosphoric acid [e.g.dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.],dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphaticcarboxylic acid [e.g. acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylicacid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; anactivated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.cyanomethyl ester, methoxymethyl ester, dimethyliminiomethyl [(CH₃)₂ N⁺═CH--] ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester,etc.], or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.], and the like. These reactive derivatives can optionally beselected from them according to the kind of the compound (II) to beused.

Suitable salts of the compound (II) and its reactive derivative may be abase salt such as an alkali metal salt [e.g. sodium salt, potassiumsalt, etc.], an alkaline earth metal salt [e.g. calcium salt, magnesiumsalt, etc.], an ammonium salt, an organic base salt [e.g. trimethylaminesalt, triethylamine salt, pyridine salt, picoline salt,dicyclohexylamine salt N,N'-dibenzylethylenediamine salt, etc.], or thelike.

The reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (II) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N'-carbonylbis(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride;oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate,isopropyl chloroformate, etc.]; triphenylphosphine;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;N-hydroxybenzotriazole;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal bicarbonate, tri(lower)alkylamine,pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, orthe like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

PROCESS 2

The object compound (I-b) or a salt thereof can be prepared by reactingthe compound (I-a) or its reactive derivative at the amino group, or asalt thereof with the compound (IV) or its reactive derivative at thecarboxy group, or a salt thereof.

Suitable salts of the compound (I-a) and its reactive derivative can bereferred to the ones as exemplified for the compound (III).

Suitable salts of the compound (IV) and its reactive derivative can bereferred to the ones as exemplified for the compound (II).

Suitable salts of the compound (I-b) can be referred to the ones asexemplified for the compound (I).

In case that the acyl of the symbol "R¹ " is one derived from carbamicacids, the starting compound (IV) is usually used in a form ofisocyanates.

This reaction can be carried out in substantially the same manner asProcess 1, and therefore the reaction mode and reaction conditions [e.g.reactive derivatives, solvents, reaction temperature, etc.] of thisreaction are to be referred to those as explained in Process 1.

PROCESS 3

The object compound (I) or a salt thereof can be prepared by reactingthe compound (V) or its reactive derivative at the carboxy group, or asalt thereof with the compound (VI) or its reactive derivative at theamino group, or a salt thereof.

Suitable salts of the compound (V) and its reactive derivative can bereferred to the ones as exemplified for the compound (II).

Suitable salts of the compound (VI) and its reactive derivatives can bereferred to the ones as exemplified for the compounds (I) and (III),respectively.

This reaction can be carried out in substantially the same manner asProcess 1, and therefore the reaction mode and reaction conditions [e.g.reactive derivatives, solvents, reaction temperature, etc.] of thisreaction are to be referred to those as explained in Process 1.

PROCESS 4

The object compound (I-d) or a salt thereof can be prepared bysubjecting a compound (I-c) or a salt thereof to removal reaction of thecarboxy-protective group in R⁵ _(a).

Suitable salts of the compounds (I-c) and (I-d) can be referred to theones as exemplified for the compound (I).

This reaction is carried out in accordance with a conventional methodsuch as solvolysis including hydrolysis, reduction or the like.

The solvolysis is preferably carried out in the presence of a base or anacid including Lewis acid.

Suitable base may include an inorganic base and an organic base such asan alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal[e.g. magnesium, calcium, etc.], the hydroxide or carbonate orbicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine,triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]-non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, orthe like.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.],an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuricacid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc.].

The removal reaction using Lewis acid such as trihaloacetic acid [e.g.trichloroacetic acid, trifluoroacetic acid, etc.] or the like, ispreferably carried out in the presence of cation trapping agents [e.g.anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride, chloroform,carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, a mixturethereof or any other solvent which does not adversely influence thereaction. A liquid base or acid can be also used as the solvent. Thereaction temperature is not critical and the reaction is usually carriedout under cooling to heating.

The reduction method applicable for the removal reaction may includechemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of metal [e.g. tin, zinc, iron, etc.] or metallic compound[e.g. chromium chloride, chromium acetate, etc.] and an organic orinorganic acid [e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts [e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.], palladium catalysts [e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.], nickel catalysts[e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobaltcatalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts[e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reducedcopper, Raney copper, Ullman copper, etc.] and the like.

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.Additionally, in case that the above-mentioned acid to be used inchemical reduction are in liquid, they can also be used as a solvent.Further, a suitable solvent to be used in catalytic reduction may be theabove-mentioned solvent, and other conventional solvent such as diethylether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to heating.

PROCESS 5

The object compound (I-f) or a salt thereof can be prepared bysubjecting the compound (I-e) or a salt thereof to removal reaction ofthe imino- or amino-protective group(s) in R² _(a).

Suitable salts of the compounds (I-e) and (I-f) can be referred to theones as exemplified for the compound (I).

This removal reaction can be carried out by a conventional method in thepeptide chemistry such as solvolysis, reduction, and the like, thedetails of which can be referred to those of Process 4.

PROCESS 6

The object compound (I-h) or a salt thereof can be prepared bysubjecting the compound (I-g) or a salt thereof to removal reaction ofthe amino-protective group in R¹ _(a).

Suitable salts of the compounds (I-g) and (I-h) can be referred to theones as exemplified for the compound (I).

This removal reaction can be carried out by a conventional method in thepeptide chemistry such as solvolysis, reduction, and the like, thedetails of which can be referred to those of Process 4.

PROCESS 7

The object compound (I-j) or a salt thereof can be prepared by reactingthe compound (I-i) or its reactive derivative at the carboxy group, or asalt thereof with an optionally substituted amine, or a salt thereof.

Suitable salts of the compound (I-i) and its reactive derivative can bereferred to the ones as exemplified for the compound (II).

Suitable salts of the compound (I-j) can be referred to the ones asexemplified for the compound (I).

Suitable optionally substituted amines means the ones which can formaforementioned amidated carboxy of R⁵ _(d) in the resulting compound(I-j).

This reaction can be carried out in substantially the same manner asProcess 1, and therefore the reaction mode and reaction conditions [e.g.reactive derivatives, solvents, reaction temperature, etc.] of thisreaction are to be referred to those as explained in Process 1.

PROCESS 8

The compound (I-g) or a salt thereof can be prepared by acylating theamino group in R¹ _(b) of the compound (I-h) or a salt thereof.

Suitable salts of the compounds (I-g) and (I-h) may be the same as thosefor the compound (I).

Suitable acylating agent used in this reaction may be a conventionalacylating agent which is capable of introducing the acyl group asmentioned before such as carboxylic acid, carbonic acid, sulfonic acidand their reactive derivative, for example, an acid halide, an acidanhydride, an activated amide, an activated ester, and the like.Preferable example of such reactive derivative may include acidchloride, acid bromide, a mixed acid anhydride with an acid such assubstituted phosphoric acid (e.g. dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, alkyl carbonate (e.g. methylcarbonate, ethyl carbonate, propyl carbonate, etc.), aliphaticcarboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.), aromatic carboxylicacid (e.g. benzoic acid, etc.), a symmetrical acid anhydride, anactivated acid amide with a heterocyclic compound containing iminofunction such as imidazole, 4-substituted imidazole, dimethylpyrazole,triazole and tetrazole, an activated ester (e.g. p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyridyl ester, piperidinyl ester, 8-quinolyl thioester, or an ester witha N-hydroxy compound such as N,N-dimethylhydroxylamine,1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide,1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.), and thelike.

This reaction can be carried out in the presence of an organic orinorganic base such as alkali metal (e.g. lithium, sodium potassium,etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride(e.g. sodium hydride, etc.), alkaline earth metal hydride (e.g. calciumhydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassiumhydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate,potassium carbonate, etc.), alkali metal bicarbonate (e.g. sodiumbicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g.sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.),alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkylamine(e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lutidine,picoline, 4-dimethylaminopyridine, etc.), quinoline, and the like.

In case that the acylating agent is used in a free form or its salt inthis reaction, the reaction is preferably carried out in the presence ofa condensing agent such as a carbodiimide compound [e.g.N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.], a keteniminecompound (e.g. N,N'-carbonylbis(2-methylimidazole),pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ethercompounds (e.g. ethoxyacetylene, β-chlorovinylethyl ether), a sulfonicacid ester of N-hydroxybenzotriazole derivative [e.g.1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, etc.], acombination of trialkylphosphite or triphenylphosphine and carbontetrachloride, disulfide or diazenedicarboxylate (e.g. diethyldiazenedicarboxylate, etc.), a phosphorus compound (e.g. ethylpolyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorustrichloride, etc.), thionyl chloride, oxalyl chloride,N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-3-sulfonate, areagent (referred to a so-called "Vilsmeier reagent") formed by thereaction of an amide compound such as N,N-di(lower)alkylformamide (e.g.dimethylformamide, etc.), N-methylformamide or the like with a halogencompound such as thionyl chloride, phosphoryl chloride, phosgene or thelike.

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction such as water, acetone,dichloromethane, alcohol (e.g. methanol, ethanol, etc.),tetrahydrofuran, pyridine, N,N-dimethylformamide, etc., or a mixturethereof.

The reaction temperature is not critical and the reaction is usuallycarried out under from cooling to heating.

PROCESS 9

The object compound (I-a) or a salt thereof can be prepared bysubjecting the compound (I-b) or a salt thereof to a removal reaction ofthe acyl group of R¹ _(c).

This removal reaction can be carried out by a conventional method in thepeptide chemistry such as solvolysis, reduction, and the like, thedetails of which can be referred to those of Process 4.

PROCESS 10

The object compound (I-l) or a salt thereof can be prepared bysubjecting a compound (I-k) or a salt thereof to removal reaction of thecarboxy-protective group in R⁴ _(c).

Suitable salts of the compound (I-k) and (I-l) can be referred to onesas exemplified for the compound (I).

This removal reaction can be carried out by a conventional method in thepeptide chemistry such as solvolysis, reduction, and the like, thedetails of which can be referred to those of Process 4.

PROCESS 11

The object compound (I-n) or a salt thereof can be prepared bysubjecting a compound (I-m) or a salt thereof to removal reaction of theimino-protective group in R³ _(a).

Suitable salts of the compound (I-m) and (I-n) can be referred to onesas exemplified for the compound (I).

This removal reaction can be carried out by a conventional method in thepeptide chemistry such as solvolysis, reduction, and the like, thedetails of which can be referred to those of Process 4.

PROCESS 12

The object compound (I-p) or a salt thereof can be prepared bysubjecting a compound (I-o) or a salt thereof to removal reaction of theamino or imino-protective group in R⁴ _(a).

Suitable salts of the compound (I-o) and (I-p) can be referred to onesas exemplified for the compound (I).

This removal reaction can be carried out by a conventional method in thepeptide chemistry such as solvolysis, reduction, and the like, thedetails of which can be referred to those of Process 4.

The compounds obtained by the above processes can be isolated andpurified by a conventional method such as pulverization,recrystallization, column chromatography, reprecipitation, or the like.

The object compound (I) can be transformed into its salt in aconventional manner.

The method for preparing the new starting compounds are explained indetail in the following.

METHOD 1 Step 1

The compound (III-a) or a salt thereof can be prepared by reacting thecompound (VII) or its reactive derivative at the carboxy group, or aslat thereof with the compound (VI) or its reactive derivative at theamino group, or a salt thereof.

Suitable salts of the compound (VII) and its reactive derivative can bereferred to the ones as exemplified for the compound (II).

Suitable salts of the compound (VIII) and its reactive derivative can bereferred to the ones as exemplified for the compound (III).

This reaction can be carried out in substantially the same manner asProcess 1, and therefore the reaction mode and reaction conditions [e.g.reactive derivatives, solvents, reaction temperature, etc.] of thisreaction are to be referred to those as explained in Process 1.

Step 2

The compound (II) or a salt thereof can be prepared by subjecting thecompound (III-a) or a salt thereof to a removal reaction of theamino-protective group of R⁸ in a conventional manner such as thoseexplained in Process 4.

METHOD 2 Step 1

The compound (IX) or a salt thereof can be prepared by reacting thecompound (II) or its reactive derivative at the carboxy group, or a saltthereof with the compound (VIII) or its reactive derivative at the aminogroup, or a salt thereof.

Suitable salts of the compound (IX) can be referred to the ones asexemplified for the compound (I).

This reaction can be carried out in substantially the same manner asProcess 1, and therefore the reaction mode and reaction conditions [e.g.reactive derivatives, solvents, reaction temperature, etc.]of thisreaction are to be referred to those as explained in Process 1.

Step 2

The compound (V) or a salt thereof can be prepared by subjecting thecompound (IX) or a salt thereof to a removal reaction of thecarboxy-protective group of R⁹ in a conventional manner such as thoseexplained in Process 4.

It is to be noted that the compound (I) and the other compounds mayinclude one or more stereoisomers due to asymmetric carbon atoms, andall of such isomers and mixture thereof are included within the scope ofthis invention.

The object compound (I) and a pharmaceutically acceptable salt thereofhave pharmacological activities such as endothelin antagonisticactivity, for example, relaxating activity of blood vessel, and thelike, and useful for therapeutical treatment and prevention ofendothelin mediated diseases such as hypertension, heart disease such asangina pectoris, cardiomyopathy, myocardial infarction or the like,cerebral stroke such as cerebral arterial spasm, cerebral ischemia,cerebrovascular twitch or the like, late phase cerebral spasm aftersubarachnoid hemorrhage, asthma such as bronchoconstriction or the like,renal failure such as acute renal failure, renal insufficiency caused bypharmaceuticals (e.g. Cisplatin, Cyclosporins, etc.), peripheralcirculatory failure, such as Raynaud'd disease, Buerger's disease, etc,arterisclerosis, diabetic nephropathy, diabetic retinopathy, shock suchas hemorrhagic shock, shock induced by endotoxins, etc,hemangioendothelioma, organopathy after re-perfusion [e.g. after organand tissue transplantation, percutaneous transluminal coronaryangiopathy (PTCA), or percutaneous transluminal coronary recanalization(PTCR), etc.], bloodstream disturbance after an operation, ulcer,irritable bowel syndrome (IBS), dysuria, retionopathy, dysmenorrheal,premature birth such as premature labor, threatened abortion, or thelike, glaucoma, re-occusion after operation of PTCA, and the like.

For therapeutic purpose, the peptide compound (I) and a pharmaceuticallyacceptable salt thereof of the present invention can be used in a formof pharmaceutical preparation containing one of said compounds, as anactive ingredient, in admixture with a pharmaceutically acceptablecarrier such as an organic or inorganic solid or liquid excipientsuitable for oral, parenteral or external administration. Thepharmaceutical preparations may be capsules, tablets, dragees, granules,solution, suspension, emulsion, sublingual tablet, suppositories,ointment, aerosol, infusion, ophthalmic solutions, vaginal suppository,and the like. If desired, there may be included in these preparations,auxiliary substances, stabilizing agents, wetting or emulsifying agents,buffers and other commonly used additives.

While the dosage of the compound (I) will vary depending upon the ageand condition of the patient, in the case of intravenous administration,a daily dose of 0.01-100 mg of the active ingredient per kg weight ofhuman being, in the case of intramuscular administration, a daily doseof 0.05-100 mg of the same per kg weight of human being, in case of oraladministration, a daily dose of 0.1-100 mg of the same per kg weight ofhuman being is generally given for the treatment of endothelin-mediateddiseases.

In order to illustrate the usefulness of the object compound (I), thepharmacological test data of some representative compounds of thecompound (I) are shown in the following.

Test 1 Radioligand Binding Assay

(1) Test Compounds

a. Compound A [The compound of Example 7-2)]

b. Compound B [The compound of Example 296]

c. Compound C [The compound of Example 325]

d. Compound D [The compound of Example 319]

e. Compound E [The compound of Example 379]

(2) Test Method

(a) Crude receptor membrane preparation

Porcine aorta was purchased from Pel-Freez Biologicals (U.S.A.) andstored at -80° C. until use.

Porcine aorta (50 g) was thawed and dissected free from fatty tissue,minced with scissors and then homogenized with a polytron (BrinkmannPT-20, maximal speed for 3×10 sec) in 100 ml buffer (0.25 M sucrose, 10mM Tris-HCl, 0.1 mM EDTA).

The homogenate was centrifuged at 10,000 g for 20 minutes at 4° C.

The supernatant, containing the plasma membrane fraction, wascentrifuged at 100,000 g for 60 minutes at 4° C., and then resultantpellets were referred to as crude membrane fractions.

The pellets were resuspended in 25 ml of binding assay buffer (50 mMTris-HCl, 100 mM NaCl, 5 mM MgCl₂, 1.5 μg/ml phenylmethylsulfonylfluoride (PMSF), 120 μg/ml bacitracin, 12 μg/ml leupepcin, 6 μg/mlchymostain, 0.1% bovine serum albumin (BSA), pH 7.5).

The aorta membrane fractions were stored at -80° C. until use.

(b) ¹²⁵ I-endothelin-1 binding assay:

¹²⁵ I-Endothelin-1 (1.67×10⁻¹¹ M) (Amersham Japan, specific activity:2000 Ci/m mol) was incubated with 50 μl of aorta membrane preparation inbinding assay buffer at room temperature (20-22° C.) for 60 minutes in afinal volume of 250 μl.

After incubation, the incubation mixture were filtered throughGlass-fiber GF/C filter (pretreated with 0.1% polyethylene imine for 3hours prior to use) using cell harvester (Brandel M-24S). The filterswere then washed ten times with a total of 3 ml of the washing buffer(50 mM Tris-HCl, pH 7.5) at 0° C. The filters were counted in a gammacounter (Packard Auto Gamma Model 5650).

(3) Test Results

The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Effect on specific binding of                                                 .sup.125 I-endothelin-1                                                       in porcine aorta membrane                                                     Test Compound   IC.sub.50 (M)                                                 ______________________________________                                        A               2.3 × 10.sup.-9                                         B               3.2 × 10.sup.-8                                         C               7.6 × 10.sup.-9                                         D               2.1 × 10.sup.-8                                         E               7.6 × 10.sup.-9                                         ______________________________________                                    

Test 2 Effect on Rabbit Aorta or Contraction Response of Endothelin

(1) Test Compound

Test Compound A

(2) Test Method

Thoracic aorta were isolated from freshly killed male albino rabbits (11weeks old) and cut into 25 mm strips with the intima denuded. Afterremoving fatty tissues, these arterial segments (2 mm width and 25 mmlength) were suspended in 25 ml organ chambers filled with Krebs-Ringersolution (113 mM NaCl, 4.8 mM KCl, 2.2 mM CaCl₂, 1.2 mM MgCl₂, 25 mMNaHCO₃, 1.2 mM KH₂ PO₄, 5.5 mM glucose) maintained at 37° C. and gassedwith 95% O₂ /5% CO₂.

A preload of 0.5 g was applied after the aorta had been conditioned byapplication of increasing concentration of KCl. Contractions weremeasured as an increase in isometric tension.

Test Compound was tested against contractile response of rabbit aortainduced by endothelin (3.2×10⁻⁹ M). Synthetic endothelin was obtainedfrom Peptide Institute Inc. (Osaka, Japan). Test Compound was addedafter the full contraction response induced by endothelin.

(3) Test Result

The activity of Test Compound is expressed as the IC₅₀ value of maximumcontraction response induced by endothelin and shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Effect on the contractile responses of rabbit                                 thoracic aorta induced by endothelin                                                       Inhibition against contraction                                   Test Compound                                                                              response of endothelin (IC.sub.50)                               ______________________________________                                        A            2.3 × 10.sup.-7 M                                          ______________________________________                                    

Test 3 Effect on Endothelin-1-Pressor Response

(1) Test Compound

Test Compound A

(2) Test Method

Wistar rats, weighing 200 g to 250 g, were anesthetized with ether, andthe abdominal aorta was canulated with a polyethylene tube via thefemoral artery and vein for blood pressure measurement and intravenousinjection of endothelin-1. The animals were allocated to recover for 3hours and tethered in each cage.

The blood pressure was directly monitored via pressure transducer(PT-200T, made by Nihon Kohden) and were recorded on a pre-writingrecorder (CWT685G, made by Nihon Kohden). Pressor response tointravenous injection of endothelin-1 (3.2 μg/kg) was obtained.

This dose produced a sustained pressor response which continued over 1hour.

The effect of intravenous injection of the Test Compound was studied inrats 20 minutes after starting an intravenous injection of endothelin-1.

(3) Test Result

Potency of the Test Compound in rats was expressed by the followingindex.

    ______________________________________                                        Test Compound  Dose (mg/kg)                                                                              Response                                           ______________________________________                                        A              10          ++                                                 ______________________________________                                         ++: completely antagonized almost (100%)                                      +: moderately antagonized (about 50%)                                         -: no effect                                                             

From the results of the above-mentioned biological test, it is clearthat compound (I) has endothelin antagonistic activity, therefore areuseful for the treatment and prevention of endothelin mediated diseases,for example, hypertension, heart disease such as angina pectoris,cardiomyopathy, myocardial infarction or the like, cerebral stroke suchas cerebral arterial spasm, cerebral ischemia, cerebrovascular twitch orthe like, late phase cerebral spasm after subarachnoid hemorrhage,asthma such as bronchoconstriction or the like, renal failure such asacute renal failure, renal insufficiency caused by pharmaceuticals (e.g.Cisplatin, Cyclosporins, etc.), or the like.

The following examples are given for purpose of illustrating the presentinvention in detail.

In these examples, there are employed the following abbreviations inaddition to the abbreviations adopted by the IUPAC-IUB.

Ac: acetyl

Boc: t-butoxycarbonyl

Bu: butyl

Bzl: benzyl

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

Et: ethyl

HOBT: N-hydroxybenzotriazole

Me: methyl

NMM: N-methylmorpholine

Pac: phenacyl

D-Pya: D-(2-pyridyl)alanine

D-4Pya: D-(4-pyridyl)alanine

TFA: trifluoroacetic acid

TEA: triethylamine

Ts or Tos: tosyl

WSCD: 1-ethyl-3-(3-dimethylaminopropyl)

carbodiimide

Z: benzyloxycarbonyl

DMAP: dimethylaminopyridine

PREPARATION 1-1)

To a mixture of Boc-D-Trp(CH₃)-OH (1.59 g), HCl·H-D-Phe-OCH₃ (1.08 g)and HOBT (0.81 g) in DMF (20 ml) was added WSCD (0.93 g) under ice-bathcooling. After being stirred for 2 hours at room temperature, themixture was concentrated in vacuo and the residue was dissolved in ethylacetate (50 ml). The solution was washed with 0.5N hydrochloric acid (20ml), water (20 ml), saturated sodium bicarbonate (20 ml) and water (20ml×2) successively, dried over magnesium sulfate and evaporated invacuo. The residue was triturated with ether to giveBoc-D-Trp(CH₃)-D-Phe-OCH₃ (1.45 g).

mp: 95-96° C.

Rf: 0.83 (CHCl₃ :MeOH=9:1).

PREPARATION 1-2)

A solution of Boc-D-Trp(CH₃)-D-Phe-OCH₃ (1.40 g) in a mixture of anisole(1.4 ml) and TFA (14 ml) was stirred for one hour at 0° C. The mixturewas concentrated in vacuo and dissolved in 4N HCl in 1,4-dioxane (10 ml)and the solution was concentrated in vacuo. The residue was trituratedwith ether to give HCl·H-D-Trp(CH₃)-D-Phe-OCH₃ (1.09 g).

mp: 188-192° C.

Rf: 0.51 (CHCl₃ MeOH=9:1).

PREPARATION 1-3)

Phenylacetyl chloride (5.7 ml) was added dropwise to a mixture ofTsOH·H-L-Leu-OBzl (14.15 g) and TEA (12 ml) in dichloromethane (300 ml)under ice-bath cooling. After being stirred for 10 minutes at the sametemperature, the mixture was concentrated in vacuo, and the residue wasdissolved in ethyl acetate (300 ml). The solution was washed with 1N HCl(100 ml), water (100 ml), 1M aqueous sodium bicarbonate (100 ml), andbrine (100 ml×2), dried over magnesium sulfate and evaporated to giveN-phenylacetyl-L-Leu-OBzl (14 g). This product was used in a next stepwithout further purification.

Rf: 0.50 (CHCl_(3:) MeOH=9:1).

PREPARATION 1-4)

A solution of N-phenylacetyl-L-Leu-OBzl (14 g) in methanol (140 ml) washydrogenated over 10% palladium on carbon (1.4 g) at 3 atmosphericpressure of hydrogen for 2 hours. After removal of the catalyst byfiltration, the filtrate was concentrated in vacuo. The residue wastriturated with diisopropyl ether to give N-phenylacetyl-L-Leu-OH (7.7g).

mp: 135-136° C.

Rf: 0.17 (CHCl₃ :MeOH=9:1).

PREPARATION 2-1)

Boc-D-Trp(CH₃)-D-Phe-OBzl was obtained in 87.2% yield in substantiallythe same manner as that of Preparation 1-1).

Rf: 0.77 (CHCl₃ :MeOH=9:1).

PREPARATION 2-2)

HCl·H-D-Trp(CH₃)-D-Phe-OBzl was obtained quantitatively in substantiallythe same manner as that of Preparation 1-2).

mp: 147-150° C.

Rf: 0.57 (CHCl₃ :MeOH=9:1).

PREPARATION 3-1)

Boc-L-Leu-OH (1.30 g), HCl·H-D-Trp(CH₃)-OBzl (1.76 g), WSCD (950 mg) andHOBT (827 mg) in DMF (30 ml) was reacted at 5° C. overnight in a similarmanner to that of Preparation 1-1) to give Boc-L-Leu-D-Trp(CH₃)-OBzl(2.48 g).

mp: 124-126° C.

Rf: 0.87 (CHCl₃ :MeOH=9:1).

PREPARATION 3-2)

Boc-L-Leu-D-Trp(CH₃)-OBzl (2.40 g) in MeOH (50 ml) and water (1 ml) washydrogenated over 10% palladium on carbon in a similar manner to that ofPreparation 1-4) to give Boc-L-Leu-D-Trp(CH₃)-OH (1.95 g).

mp: 64-67° C.

Rf: 0.57 (CHCl₃ :MeOH:AcOH=16:1:1).

PREPARATION 4-1)

N-Phenylacetyl-L-Leu-D-Trp(CH₃)-OBzl (5.96 g) was obtained fromN-phenylacetyl-L-Leu-OH (2.96 g), HCl·H-D-Trp(CH₃)-OBzl (3.9 g), HOBT(1.68 g) and WSCD (1.93 g) in a similar manner to that of Preparation1-1).

mp: 152-155° C.

Rf: 0.72 (CHCl₃ :MeOH=9:1).

PREPARATION 4-2)

To a solution of N-phenylacetyl-L-Leu-D-Trp(CH₃)-OBzl (5.9 g) in amixture of methanol (60 ml), acetic acid (60 ml) and DMF (100 ml) wasadded 10% palladium on activated carbon (0.6 g). The mixture was stirredfor 5 hours at 3 atmospheric pressure of hydrogen at room temperature.The solution was filtered and the filtrate was concentrated in vacuo.The residue was triturated with ether-ethyl acetate to giveN-phenylacetyl-L-Leu-D-Trp(CH₃)-OH (4.69 g).

mp: 76-79° C.

Rf: 0.50 (CHCl₃ :MeOH:AcOH=16:1:1).

PREPARATION 5

Boc-D-Trp(CH₃)-OH (6.0 g), D-Pya-OC₂ H₅ ·2HCl (5.54 g), WSCD (3.51 g),HOBT (3.05 g) and TEA (2.09 g) were reacted in DMF (200 ml) in a similarmanner to that of Preparation 1-1) to give Boc-D-Trp(CH₃)-D-Pya-OC₂ H₅(6.18 g).

mp: 99-101° C.

Rf: 0.67 (CHCl₃ :MeOH=9:1).

PREPARATION 6

Boc-D-Trp(CH₃)-D-Pya-OC₂ H₅ (4 50 g), TFA (50 ml) and anisole (5 ml)were reacted in a similar manner to that of Preparation 1-2) to give2HCl·H-D-Trp(CH₃)-D-Pya-OC₂ H₅ (4.15 g).

mp: 81-83° C.

Rf: 0.22 (CHCl₃ :MeOH:AcOH=8:1:1).

PREPARATION 7

To a solution of (S)-α-benzyloxycarbonyl-γ-methylbutyl isocyanate (1.50g) in ethyl acetate (60 ml) was added hexahydro-1H-azepine (722 mg) atroom temperature. After being stirred for 30 minutes at the sametemperature, the solution was washed with 5% HCl, 1M sodium bicarbonatesolution and saturated sodium chloride solution successively, and driedover anhydrous magnesium sulfate. The solution was concentrated in vacuoto give N-(hexahydro-1H-azepin-1-ylcarbonyl)-L-Leucine benzyl ester(2.06 g) as a crystal.

mp: 79-82° C.

Rf: 0.64 (n-hexane:EtOAc=1:1).

PREPARATION 8

(2S)-2-Amino-3,3-dimethyl-N,N-dimethylbutyramide hydrochloride (0.20 g),(S)-α-benzyloxycarbonyl-γ-methylbutyl isocyanate (0.25 g) and TEA (0.1ml) were reacted in ethyl acetate (10 ml) in a similar manner to that ofPreparation 7 to give N-[(1S)-2,2-dimethyl-1-(N,N-triturateddimethylcarbamoyl)propyl]carbamoyl]-L-Leu-OBzl (0.40 g).

Rf: 0.59 (hexane:EtOAc=2:1).

PREPARATION 9

(S)-α-Benzyloxycarbonyl-γ-methylbutyl isocyanate (500 mg) andoctahydroazocine (275 mg) were reacted in a similar manner to that ofPreparation 7 to give N-(octahydroazocin-1-ylcarbonyl)-L-Leu-OBzl (680mg).

mp: 87-89° C.

Rf: 0.65 (n-hexane:EtOAc=1:1).

PREPARATION 10

(2S)-2-Amino-3,3-dimethyl-N,N-dimethylbutyramide hydrochloride (0.25 g),(2S)-2-chlorocarbonyloxy-4-methylvaleric acid benzyl ester (0.36 g) andTEA (0.31 g) were reacted in ethyl acetate (10 ml) in a similar mannerto that of Example 4-1) to give(2S)-2-[N-[(1S)-2,2-dimethyl-1-(N,N-dimethylcarbamoyl)propyl]carbamoyloxy]-4-methylvalericacid benzyl ester (0.44 g).

Rf: 0.42 (hexane:EtOAc=2:1).

PREPARATION 11

Benzyl (2R)-2-carboxymethyl-4-methylvalerate (1.35 g),hexahydro-1H-azepine (0.610 g) and WSCD·HCl (1.18 g) were reacted inmethylene chloride (30 ml) in a similar manner to that of Preparation1-1) to give benzyl(2R)-2-(hexahydro-1H-azepin-1-ylcarbonylmethyl)-4-methylvalerate (1.65g).

Rf: 0.87 (benzene:EtOAc:AcOH=20:20:1).

PREPARATION 12

The following compounds were obtained by catalytic reduction of thecorresponding benzyl esters in a similar manner to that of Preparation4-2).

N-[(1S)-2,2-Dimethyl-1-(N,N-dimethylcarbamoyl)propyl]carbamoyl]-L-Leu-OH.

mp: 90-93° C.

Rf: 0.50 (CHCl₃ :MeOH:AcOH=16:1:1).

(2S)-2-[N-[(1S)-2,2-Dimethyl-1-(N,N-dimethylcarbamoyl)propyl]carbamoyloxy]-4-methylvalericacid.

mp: 146-148° C .

Rf: 0.20 (CHCl₃ :MeOH=9:1).

N-(Hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-OH.

Rf: 0.40 (benzene:EtOAc:AcOH=20:20:1).

4) (2R)-2-(Hexahydro-1H-azepin-1-ylcarbonylmethyl)-4-methylvaleric acid.

Rf: 0.55 (benzene:EtOAc:AcOH=20:20:1).

N-(Octahydroazocin-1-ylcarbonyl)-L-Leu-OH.

Rf: 0.45 (benzene:EtOAc:AcOH=20:20:1)

PREPARATION 13

The following compounds could be obtained by reacting the correspondingstarting compounds with 2HCl·H-D-Pya-OC₂ H₅ in the presence of NMM in asimilar manner to that of Preparation 1-1).

1) Boc-D-Trp(i-C₄ H₉)-D-Pya-OC₂ H₅

mp: 60-62° C.

Rf: 0.62 (CHCl₃ :MeOH=9:1)

2) Boc-D-Trp(CHO)-D-Pya-OC₂ H₅

mp: 131-134° C.

Rf: 0.60 (CHCl₃ :MeOH=9:1).

Boc-D-Trp(C₂ H₅)-D-Pya-OC₂ H₅.

mp: 64-67° C.

Rf: 0.61 (CHCl₃ :MeOH=9:1).

4) Boc-D-Trp(n-C₃ H₇)-D-Pya-OC₂ H₅.

mp: 62-63° C.

Rf: 0.60 (CHCl₃ :MeOH=9:1).

PREPARATION 14

The following compounds could be obtained by removingtert-butoxycarbonyl groups from the corresponding starting compoundswith TFA and anisole in a similar manner to that of Preparation 1-2).

1) 2HCl·H-D-Trp(i-C₄ H₉)-D-Pya-OC₂ H₅

Rf: 0.09 (CHCl₃ :MeOH=9:1). 2) 2HCl·H-D-Trp(CHO)-D-Pya-OC₂ H₅

Rf: 0.15 (CHCl₃ :MeOH=9:1).

3) HCl·H-D-Trp(C₂ H₅)-D-Pya-OC₂ H₅

Rf: 0.15 (CHCl₃ :MeOH=9:1).

4) HCl·H-D-Trp(n-C₃ H₇)-D-Pya-OC₂ H₅

Rf: 0.13 (CHCl₃ :MeOH=9:1).

PREPARATION 15

The following compounds could be obtained by reacting(S)-α-benzyloxycarbonyl-γ-methylbutyl isocyanate with the correspondingamines in a similar manner to that of Preparation 7.

1) N-(Thiomorpholinocarbonyl)-L-Leu-OBzl

mp: 89-91° C.

Rf: 0.53 (n-hexane:AcOEt=1:1).

2) N-(1,2,3,4-Tetrahydroisoquinolin-2-ylcarbonyl)-L-Leu-OBzl

Rf: 0.71 (n-hexane:AcOEt=1:1).

3) N-(1,2,3,4-Tetrahydroquinolin-1-ylcarbonyl)-L-Leu-OBzl

Rf: 0.62 (n-hexane:AcOEt=2:1).

4) N-(N,N-Dibutylcarbamoyl)-L-Leu-OBzl

Rf: 0.70 (n-hexane:AcOEt=2:1).

5) N-(N,N-Dipropylcarbamoyl)-L-Leu-OBzl

Rf: 0.69 (n-hexane:AcOEt=2:1).

6) N-(N-Heptylcarbamoyl)-L-Leu-OBzl

Rf: 0.63 (n-hexane:AcOEt=2:1).

7) N-(N,N-Diisobutylcarbamoyl)-L-Leu-OBzl

Rf: 0.76 (n-hexane:AcOEt=2:1).

8) N-(N-Cyclohexyl-N-methylcarbamoyl)-L-Leu-OBzl

Rf: 0.82 (n-hexane:AcOEt=1:1).

9) N-[4-(N,N-Dimethylcarbamoyl)piperidinocarbonyl]-L-Leu-OBzl

Rf: 0.53 (CHCl₃ :MeOH:AcOH=16:1:1).

10) N-(2-Pyridylcarbamoyl)-L-Leu-OBzl

Rf: 0.61 (CHCl₃ :MeOH=9:1).

11) N-[(2S)-2-(N,N-Dimethylcarbamoyl)pyrrolidin-1-ylcarbonyl)-L-Leu-OBzl

Rf: 0.47 (CHCl₃ :MeOH=9:1).

12) N-[(2R)-2-(N,N-Dimethylcarbamoyl)pyrrolidin-1-ylcarbonyl)-L-Leu-OBzl

Rf: 0.51 (CHCl₃ :MeOH=9:1).

13) N-[1-(N,N-Dimethylcarbamoyl)cyclohexylcarbamoyl]L-Leu-OBzl

mp: 145-148° C.

Rf: 0.61 (CHCl₃ :MeOH=9:1).

14)N-[(1S,2S)-1-(N,N-Diethylcarbamoyl)-2-methylbutylcarbamoyl]-L-Leu-OBzl

Rf: 0.31 (n-hexane:AcOEt=2:1).

15) N-(1,2,3,6-Tetrahydropyridin-1-ylcarbonyl)-L-Leu-OBzl

Rf: 0.49 (n-hexane:AcOEt=2:1).

16) N-(2,6-Dimethylpiperidinocarbonyl)-L-Leu-OBzl

mp: 81-83° C.

Rf: 0.53 (n-hexane:AcOEt=2:1).

17) N-(3,5-Dimethylpiperidinocarbonyl)-L-Leu-OBzl

Rf: 0.60 (n-hexane:AcOEt=2:1).

18) N-(N,N-Dicyclohexylcarbamoyl)-L-Leu-OBzl

mp: 100-103° C.

Rf: 0.80 (n-hexane:AcOEt=2:1).

19) N-(N,N-Diethylcarbamoyl)-L-Leu-OBzl

Rf: 0.45 (n-hexane:AcOEt=2:1).

20) N-(N,N-Diisopropylcarbamoyl)-L-Leu-OBzl

Rf: 0.65 (n-hexane:AcOEt=2:1).

21)N-[N-Methyl-N-[(1S)-3-methyl-1-(N,N-dimethylcarbamoyl)butyl]carbamoyl]-L-Leu-OBzl

mp: 183-187° C.

Rf: 0.38 (CHCl₃ :MeOH:AcOH=16:1:1).

22) N-[(1S)-1-(N,N-Dimethylcarbamoyl)pentylcarbamoyl]-L-Leu-OBzl

mp: 133-136° C.

Rf:0.59 (n-hexane:AcOEt=2:1).

23)N-[N-Methyl-N-[(1S,2S)-1-(N,N-dimethylcarbamoyl)-2-methylbutyl]carbamoyl]-L-Leu-OBzl

Rf: 0.60 (n-hexane:AcOEt=2:1).

24) N-[(1S)-1-(N,N-Dimethylcarbamoyl)ethylcarbamoyl)]-L-Leu-OBzl

Rf: 0.55 (n-hexane:AcOEt=2:1).

PREPARATION 16

To a solution of benzyl (2S)-2-chlorocarbonyloxy-4-methylvalerate (0.56g) in tetrahydrofuran (11 ml) was added cyclohexylamine (0.40 g) at roomtemperature. After being stirred for 10 minutes, the solvent was removedby evaporation under reduced pressure, and the residue was dissolved inethyl acetate (30 ml). The solution was washed with 1N HCl, water andbrine successively. The organic layer was dried over magnesium sulfateand concentrated in vacuo. The residual solid was triturated with hexaneto give benzyl (2S)-2-cyclohexylcarbamoyloxy-4-methylvalerate (0.45 g).

mp: 89-90° C.

Rf: 0.70 (n-hexane:AcOEt=2:1).

PREPARATION 17

The following compounds could be obtained by reacting benzyl(2S)-2-chlorocarbonyloxy-4-methylvalerate with the corresponding aminesin a similar manner to that of Preparation 16.

1) Benzyl (2S)-4-methyl-2-[(2S)-2-methylbutylcarbamoyloxy]valerate

mp: 48-49° C.

Rf: 0.69 (n-hexane:AcOEt=2:1).

2) Benzyl(2S)-4-methyl-2-[(1S,2S)-2-methyl-1-(N,N-dimethylcarbamoyl)butylcarbamoyloxy]valerate

Rf: 0.91 (CHCl₃ :MeOH=9:1).

3) Benzyl(2S)-4-methyl-2-[(1R,2S)-2-methyl-1-(N,N-dimethylcarbamoyl)butylcarbamoyloxy]valerate

Rf: 0.36 (n-hexane:AcOEt=2:1).

4) Benzyl(2S)-4-methyl-2-[(1S)-2-methyl-1-(N,N-dimethylcarbamoyl)propylcarbamoyloxy]valerate

Rf: 0.36 (n-hexane:AcOEt=2:1).

5) Benzyl(2S)-4-methyl-2-[(1S)-3-methyl-1-(N,N-dimethylcarbamoyl)butylcarbamoyloxy]valerate

Rf: 0.37 (n-hexane:AcOEt=2:1).

6) Benzyl(2S)-4-methyl-2-[(1S,2S)-2-methyl-1-(piperidinocarbonyl)butylcarbamoyloxy]valerate

Rf: 0.36 (n-hexane:AcOEt=2:1).

7) Benzyl(2S)-4-methyl-2-[(1S,2S)-1-carbamoyl-2-methylbutylcarbamoyloxy]valerate

mp: 140-141° C.

Rf: 0.13 (n-hexane:AcOEt=2:1).

8) Benzyl(2S)-2-[(1S,2S)-1-(isopropylcarbamoyl)-2-methylbutylcarbamoyloxy]-4-methylvalerate

mp: 90-92° C.

Rf: 0.67 (n-hexane:AcOEt=2:1).

9) Benzyl (2S)-4-methyl-2-(piperidinocarbonyloxy)valerate

Rf: 0.70 (n-hexane:AcOEt=2:1).

10) Benzyl(2S)-2-[(1S,2S)-1-(cyclohexylcarbamoyl)-2-methylbutylcarbamoyloxy]-4-methylvalerate

mp : 98-100° C.

Rf: 0.55 (n-hexane:AcOEt=2:1).

11) Benzyl (2S)-2-(hexahydro-1H-azepin-1-ylcarbonyloxy)-4-methylvalerate

Rf: 0.78 (n-hexane:AcOEt=2:1)

12) Benzyl(2S)-2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyloxy)-4-methylvalerate

Rf: 0.68 (n-hexane:AcOEt=2:1)

PREPARATION 18

To a solution of benzyl (2R)-2-carboxymethyl-4-methylvalerate (527 mg)and cyclohexylamine (238 mg) in methylene chloride (10 ml) was addedWSCD·HCl (460 mg) at room temperature. After being stirred overnight,the mixture was concentrated in vacuo and the residue was dissolved inethyl acetate (30 ml). The solution was washed with 5% HCl, water,saturated sodium bicarbonate and water, dried over magnesium sulfate andevaporated in vacuo. The residue was triturated with n-hexane to givebenzyl (2R)-2-(cyclohexylcarbamoylmethyl)-4-methylvalerate (410 mg).

mp: 99-102° C.

Rf: 0.84 (benzene:AcOEt:AcOH=20:20:1).

PREPARATION 19

Benzyl (2R)-2-carboxymethyl-4-methylvalerate (320 mg), octahydroazocin(165 mg) and WSCD·HCl (280 mg) were reacted in methylene chloride (20ml) in a similar manner to that of Preparation 18 to give benzyl(2R)-2-(octahydroazocin-1-ylcarbonylmethyl)-4-methylvalerate (378 mg).

Rf: 0.83 (benzene:AcOEt:AcOH=20:20:1)

PREPARATION 20

The following compounds could be obtained by reducing the correspondingbenzyl ester compounds in the presence of 10% palladium on carbon in asimilar manner to that of Preparation 1-4).

1) N-(1,2,3,4-Tetrahydroisoquinolin-2-ylcarbonyl)-L-Leu-OH

mp: 93-95° C.

Rf: 0.32 (benzene:AcOEt:AcOH=20:20:1).

2) N-(1,2,3,4-Tetrahydroquinolin-1-ylcarbonyl)-L-Leu-OH

Rf: 0.46 (benzene:AcOEt:AcOH=20:20:1).

3) N-(N,N-Dibutylcarbamoyl)-L-Leu-OH

mp: 121-123° C.

Rf: 0.51 (benzene:AcOEt:AcOH=20:20:1).

4) N-(N,N-Dipropylcarbamoyl)-L-Leu-OH

Rf: 0.41 (benzene:AcOEt:AcOH=20:20:1).

5) N-(N-Heptylcarbamoyl)-L-Leu-OH

Rf: 0.48 (benzene:AcOEt:AcOH=20:20:1).

6) N-(N,N-Diisobutylcarbamoyl)-L-Leu-OH

mp: 116-118° C.

Rf: 0.39 (benzene:AcOEt:AcOH=20:20:1).

7) N-(N-Cyclohexyl-N-methylcarbamoyl)-L-Leu-OH

Rf: 0.51 (benzene:AcOEt:AcOH=20:20:1).

8) N-[4-(N,N-Dimethylcarbamoyl)piperidinocarbonyl]-L-Leu-OH

Rf: 0.10 (CHCl₃ :MeOH:AcOH=16:1:1).

9) N-(2-Pyridylcarbamoyl)-L-Leu-OH

Rf: 0.19 (CHCl₃ :MeOH:AcOH=16:1:1).

10) N-[(2S)-2-(N,N-Dimethylcarbamoyl)pyrrolidin-1-ylcarbonyl)-L-Leu-OH

Rf: 0.34 (CHCl₃ :MeOH:AcOH=16:1:1).

11) N-[(2R)-2-(N,N-Dimethylcarbamoyl)pyrrolidin-1-ylcarbonyl)-L-Leu-OH

Rf: 0.34 (CHCl₃ :MeOH:AcOH=16:1:1).

12) N-[1-(N,N-Dimethylcarbamoyl)cyclohexylcarbamoyl]-L-Leu-OH

mp: 191-192° C.

Rf: 0.35 (CHCl₃ :MeOH:AcOH=16:1:1).

13) N-[(1S,2S)-1-(N,N-Dimethylcarbamoyl)-2methylbutylcarbamoyl]-L-Leu-OH

Rf: 0.35 (CHCl₃ :MeOH:AcOH=16:1:1).

14) N-(2,6-Dimethylpiperidinocarbonyl)-L-Leu-OH

Rf: 0.53 (CHCl₃ :MeOH:AcOH=16:1:1).

15) N-(3,5-Dimethylpiperidinocarbonyl)-L-Leu-OH

Rf: 0.53 (CHCl₃ :MeOH:AcOH=16:1:1).

16) N-(N,N-Dicyclohexylcarbamoyl)-L-Leu-OH

mp: 62-73° C.

Rf: 0.42 (CHCl₃ :MeOH:AcOH=16:1:1).

17) N-(N,N-Diethylcarbamoyl)-L-Leu-OH

mp 106-107° C.

Rf: 0.36 (CHCl₃ :MeOH:AcOH=16:1:1).

18) N-(N,N-Diisopropylcarbamoyl)-L-Leu-OH

Rf: 0.38 (CHCl₃ :MeOH:AcOH=16:1:1).

19)N-[N-Methyl-N-[(1S)-3-methyl-1-(N,N-dimethylcarbamoyl)butyl]carbamoyl]-L-Leu-OH

Rf: 0.38 (CHCl₃ :MeOH:AcOH=16:1:1).

20) N-[(1S)-1-(N,N-Dimethylcarbamoyl)pentylcarbamoyl]-L-Leu-OH

mp: 155-160° C.

Rf: 0.34 (CHCl₃ :MeOH:AcOH=16:1:1).

21)N-[N-Methyl-N-[(1S,2S)-1-(N,N-Dimethylcarbamoyl)-2-methylbutyl]carbamoyl]-L-Leu-OH

Rf: 0.52 (CHCl₃ :MeOH:AcOH=16:1:1).

22) N-[(1S)-1-(N,N-Dimethylcarbamoyl)ethylcarbamoyl)]-L-Leu-OH

Rf: 0.46 (CHCl₃ :MeOH:AcOH=16:1:1).

23) (2S)-2-Cyclohexylcarbamoyloxy-4-methylvaleric acid

Rf: 0.45 (CHCl₃ :MeOH=9:1).

24) (2S)-4-Methyl-2-[(2S)-2-methylbutylcarbamoyloxy]valeric acid

Rf: 0.40 (CHCl₃ :MeOH=9:1).

25)(2S)-4-Methyl-2-[(1S,2S)-2-methyl-1-(N,N-dimethylcarbamoyl)butylcarbamoyloxy]valericacid

Rf: 0.50 (CHCl₃ :MeOH:AcOH=16:1:1).

26)(2S)-4-Methyl-2-[(1R,2S)-2-methyl-1-(N,N-dimethylcarbamoyl)butylcarbamoyloxy]valericacid

Rf: 0.33 (CHCl₃ :MeOH:AcOH=16:1:1).

27)(2S)-4-Methyl-2-[(1S)-2-methyl-1-(N,N-Dimethyl-carbamoyl)propylcarbamoyloxy]valericacid

Rf: 0.31 (CHCl₃ :MeOH:AcOH=16:1:1).

28)(2S)-4-Methyl-2-[(1S)-3-methyl-1-(N,N-dimethylcarbamoyl)butylcarbamoyloxy]valericacid

Rf: 0.35 (CHCl₃ :MeOH:AcOH=16:1:1).

29)(2S)-4-Methyl-2-[(1S,2S)-1-carbamoyl-2-methylbutylcarbamoyloxy]valericacid

mp: 170-175° C .

Rf: 0.50 (CHCl₃ :MeOH:AcOH=16:1:1).

30)(2S)-2-[(1S,2S)-1-(Isopropylcarbamoyl)-2-methylbutylcarbamoyloxy]-4-methylvalericacid

mp: 179-180° C.

Rf: 0.37 (CHCl₃ :MeOH:AcOH=16:1:1).

31) (2S)-4-Methyl-2-(Piperidinocarbonyloxy)valeric acid

Rf: 0.56 (CHCl₃ :MeOH:AcOH=16:1:1).

32)(2S)-2-[(1S,2S)-1-(Cyclohexylcarbamoyl)-2-methylbutylcarbamoyloxy]-4-methylvalericacid

mp: 193-195° C.

Rf: 0.43 (CHCl₃ :MeOH:AcOH=16:1:1).

33) (2S)-2-(Hexahydro-1H-azepin-1-ylcarbonyloxy)-4-methylvaleric acid

mp: 86-88° C.

Rf: 0.53 (benzene:AcOEt:AcOH=20:20:1).

34)(2S)-2-(1,2,3,4-Tetrahydroisoquinolin-2-ylcarbonyloxy-4-methylvalericacid

Rf: 0.48 (benzene:AcOEt:AcOH=20:20:1).

35) (2R)-2-(Cyclohexylcarbamoylmethyl)-4-methylvaleric acid

mp: 86-88° C.

Rf: 0.53 (benzene:AcOEt:AcOH=20:20:1).

36) (2R)-2-(Octahydroazocin-1-ylcarbonylmethyl)-4-methylvaleric acid

mp: 79-81° C.

Rf: 0.56 (benzene:AcOEt:AcOH=20:20:1).

37) N-Cyclohexylcarbamoyl-L-Leu-OH

mp: 105-108° C.

Rf: 0.32 (CHCl₁₃ :MeOH=9:1).

38) N-[1-(N,N-Dimethylcarbamoylmethyl)cyclohexylcarbamoyl]-L-Leu-OH

Rf: 0.35 (CHCl₃ :MeOH:AcOH=16:1:1).

39) N-Cyclohexylcarbamoyl-L-Leu-D-Trp(CH3)-OH

mp: 202-206° C.

Rf: 0.51 (CHCl₃ :MeOH:AcOH=8:1:1).

40) N-(Piperidinocarbamoyl)-L-Leu-OH

mp: 185-187° C.

Rf: 0.70 (CHCl₃ :MeOH=9:1).

41) N-[(2S)-2-Methylbutylcarbamoyl]-L-Leu-OH

Rf: 0.22 (CHCl₃ :MeOH:AcOH=8:1:1).

42) N-(2-Pyridylmethylcarbamoyl)-L-Leu-OH

mp: 183-185° C.

Rf: 0.23 (CHCl₃ :MeOH:AcOH=8:1:1).

43)N-[(1S,2S)-1-(N,N-Dimethylcarbamoyl)-2-methylbutylcarbamoyl]-L-Leu-OH

mp: 185-187° C.

Rf: 0.27 (CHCl₃ :MeOH:AcOH=8:1:1).

PREPARATION 21

To a solution of N-(1,2,3,6-tetrahydropyridin-1-ylcarbonyl)-L-Leu-OBzl(0.58 g) in MeOH (6 ml) was added 1N NaOH (3.5 ml) at room temperature.After one hour, the mixture was acidified with 1N HCl (5 ml) and thesolvent was removed by evaporation in vacuo. The residue was dissolvedin ethyl acetate (20 ml) and washed with water 20 ml) and brine (20 ml).The organic layer was dried over magnesium sulfate and concentrated invacuo to give N-(1,2,3,6-tetrahydropyridin-1-ylcarbonyl)-L-Leu-OH (0.31g) as an oil.

Rf: 0.42 (CHCl₃ :MeOH:AcOH=16:1:1).

PREPARATION 22

The following compounds could be obtained by hydrolyzing thecorresponding benzyl ester compounds with 1N NaOH in a similar manner tothat of Preparation 21.

1) N-(Thiomorpholinocarbonyl)-L-Leu-OH

Rf: 0.31 (benzene:AcOEt:AcOH=20:20:1).

2)(2S)-2-[(1S,2S)-1-(Piperidinocarbonyl)-2-methylbutyl-carbamoyloxy]-4-methylvalericacid

Rf: 0.47 (CHCl₃ :MeOH:AcOH=16:1:1).

PREPARATION 23

L-Leu-OH (10.0 g) was dissolved in water (150 ml) containingconcentrated sulfuric acid (3.2 ml) at 0° C. To the solution was addeddropwise a solution of sodium nitrate (7.9 g) in water (50 ml) over 1hour. The mixture was saturated with sodium chloride and extracted withethyl acetate (500 ml). The organic layer was dried over magnesiumsulfate and concentrated in vacuo. The residual solid was trituratedwith hexane to give (2S)-2-hydroxy-4methylvaleric acid (6.51 g).

mp: 70-72° C.

Rf: 0.80 (n-BuOH:AcOH:H₂ O=4:1:1).

PREPARATION 24

To a stirring solution of (2S)-2-hydroxy-4-methylvaleric acid (5.0 g)and benzyl bromide (4.95 ml) in DMF (50 ml) was added potassiumcarbonate (3.13 g) at room temperature. After being stirred for 12hours, the solvent was removed by evaporation in vacuo. The residue wasdissolved in ethyl acetate (100 ml) and washed with water, 1N HCl andbrine successively. The organic layer was dried over magnesium sulfateand concentrated in vacuo. The residual oil was purified with silica gelcolumn chromatography (hexane-ethyl acetate as an eluent) to give benzyl(2S)-2-hydroxy-4-methylvalerate (8.2 g) as a colorless oil.

Rf: 0.67 (CHCl₃ :MeOH:AcOH=16:1:1).

PREPARATION 25

To a solution of benzyl (2S)-2-hydroxy-4-methylvalerate (1.00 g) intetrahydrofuran (20 ml) was added trichloromethyl chloroformate (0.55ml) at room temperature. The solution was refluxed for 11 hours and thesolvent was removed by evaporation at atmospheric pressure to givebenzyl (2S)-2-chlorocarbonyloxy-4-methylvalerate (1.26 g) as an oil.

Rf: 0.81 (n-hexane:AcOEt=2:1).

PREPARATION 26

A solution of benzyl (2R)-2-t-butoxycarbonylmethyl-4-methylvalerate(3.40 g) in TFA (60 ml) was stirred for 1 hour under ice-bath cooling.Evaporation of TFA gave benzyl (2R)-2-carboxymethyl-4-methylvalerate(2.72 g) as an oil.

Rf: 0.73 (benzene:AcOEt:AcOH=20:20:1).

PREPARATION 27

The following compounds could be obtained by reacting the correspondingstarting compounds with phenyl isocyanate in Et₃ N or NMM in a similarmanner to that of Preparation 7.

1) N-Cyclohexylcarbamoyl-L-Leu-OBzl

mp: 120-125° C.

Rf: 0.73 (CHCl₃ :MeOH=9:1).

2) N-Cyclohexylcarbamoyl-L-Leu-D-Trp(CH₃)-OBzl

mp: 190-193° C.

Rf: 0.74 (CHCl₃ :MeOH=9:1).

PREPARATION 28

The following compounds could be obtained by reacting TsOH·H-L-Leu-OBzlwith the corresponding amines in the presence of trichloromethylchloroformate in a similar manner to that of Example 72.

1) N-[1-(N,N-Dimethylaminocarbonylmethyl)cyclohexylcarbamoyl]-L-Leu-OBzl

Rf: 0.70 (CHC13:MeOH=9:1).

2)N-[(1S,2S)-1-(N,N-Dimethylcarbamoyl-2-methylbutylcarbamoyl)-L-Leu-OBzl

mp: 95-98° C.

Rf: 0.32 (n-hexane:AcOEt=1:1).

3) N-(Piperidinocarbamoyl)-L-Leu-OBzl

Rf: 0.43 (n-hexane:AcOEt=1:1).

4) N-(2-Pyridylmethylcarbamoyl)-L-Leu-OBzl

Rf: 0.50 (AcOEt).

5) N-[(2S)-2-Methylbutylcarbamoyl]-L-Leu-OBzl

mp: 73-75° C.

Rf: 0.29 (n-hexan AcOEt=3:1).

PREPARATION 29

1) A mixture of TSOH·H-L-Leu-OBzl (12.0 g), ethyl acetate (150 ml) and1M sodium bicarbonate (150 ml) was stirred at room temperature for 20minutes. The separated organic phase was washed with 1M sodiumbicarbonate and a saturated aqueous sodium chloride, and then dried overmagnesium sulfate. To this solution was added 4N hydrogen chloride inethyl acetate (15.3 ml), followed by stirring for 5 minutes underice-cooling. Removal of the solvent gave HCl·H-L-Leu-OBzl (7.66 g).

2) To a solution of the above product (7.6 g) in toluene (228 ml) wereadded charcoal (380 mg) and a solution of trichloromethyl chloroformate(3.6 ml) in toluene (7.6 ml), and the mixture was stirred at 120° C. for2 hours and then filtered. The solvent was removed from the filtrate andthe residue was dissolved in toluene (152 ml). This solution wasevaporated to give (S)-α-benzyloxycarbonyl-γ-methylbutylisocyanate (7.58g).

3) To a solution of this product in ethyl acetate (114 ml) was addedhexahydro-1H-azepin (3.5 g) under ice-cooling, and the mixture wasstirred at the same temperature for 30 minute. The resultant solutionwas washed with 5% HCl, aqueous sodium bicarbonate and saturated aqueoussodium chloride and then dried over magnesium sulfate. Removal of thesolvent gave N-(hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-OBzl (9.96 g).

Rf: 0.71 (n-hexane:EtOAc=2:1).

4) To a solution of N-(hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-OBzl (9.0g) in ethanol (69 ml) was catalytically reduced with 10% palladium oncarbon (0.692 g) under 3 atmospheric pressure of hydrogen for 30minutes. The catalyst was removed by filtration and the filtrate wasevaporated to dryness. The residue was dissolved in ethyl acetate (138ml), and this solution was washed with 5% HCl and saturated aqueoussodium chloride and then dried. Removal of the solvent gave a residue,which was crystallized from ethyl acetate and hexane to affordN-(hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-OH (5.7 g).

mp: 90-92° C.

Rf: 0.43 (benzene:EtOAc:AcOH=20:20:1).

PREPARATION 30

1) To a solution of Boc-D-Trp-OH (15.0 g) in DMF (150 ml) were addedpotassium tert-butoxide (13.8 g) and methyl iodide (10.5 g) underice-cooling. After stirring under ice-cooling for 30 minutes and at roomtemperature for 15 minutes, the reaction mixture was poured intoice-cooled 0.24 NHCl, followed by extraction with ethyl acetate. Theextract was washed with 5% NaHSO₃ and saturated aqueous sodium chloride.Removal of the solvent gave a residue, which was crystallized fromdiisopropyl ether to afford Boc-D-Trp(CH₃)-OH (9.18 g).

Rf: 0.61 (CHCl₃ :MeOH=8:2).

2) To a solution of this product (6.84 g) in dichloromethane (137 ml)were added NMM (2.17 g) and isobutyl chloroformate (2.93 g) at -30° C.Thereto was added 2HCl·H-D-Pya-OC₂ H₅ (6.0 g) at -15 to -10° C. and thenNMM (4.54 g) at -20° C., and the mixture was stirred at the sametemperature for 30 minutes. The reaction mixture was washed with 1Msodium bicarbonate and saturated aqueous sodium chloride, and thentreated with charcoal. The solvent was removed by evaporation and theresidue was crystallized from ethyl acetate and hexane to giveBoc-D-Trp(CH₃)-D-Pya-OC₂ H₅ (7.88 g).

mp: 99-101° C.

Rf: 0.80 (CHCl₃ :MeOH=9:1).

[α]²³ _(D) : +26.5° (C=1.0, MeOH).

To a solution of the above product (7.8 g) in ethyl acetate (61.7 ml)was added 4N hydrogen chloride in ethyl acetate (30.8 ml) underice-cooling, and this mixture was stirred at room temperature for anhour. The desired product was collected by decantation and trituratedwith ethyl acetate to give 2HCl·H-D-Trp(CH₃)-D-Pya-OC₂ H₅ (7 4 g).

PREPARATION 31-1)

N.sup.α -Boc-N.sup.α -methyl-N^(in) -methyl-D-Trp-OH (0.65 g),2HCl·H-D-Pya-OEt (0.52 g) HOBt (0.32 g), WSCD (0.36 g), Et₃ N (0.20 g)and DMF (20 ml) were reacted in a similar manner to that of Preparation1-1) to give N.sup.α -Boc-N.sup.α_(-methyl-N) ^(in)-methyl-D-Trp-D-Pya-OEt (0.78 g).

Rf=0.81 (CHCl₃ : MeOH=9:1).

PREPARATION 31-2)

Boc-D-Trp(CHO)-OH (2.0 g), 2HCl·H-D-Pya-OEt (1.61 g), WSCD (1.03 g),HOBt (0.90 g), NMM (0.61 g) and DMF (20 ml) were reacted in a similarmanner to that of Preparation 1-1) to give Boc-D-Trp(CHO)-D-Pya-OEt(2.23 g).

mp: 136-137° C.

Rf: 0.65 (ethyl acetate).

PREPARATION 31-3)

To a solution of Boc-D-Trp(CHO)-OH (0.79 g) and N-methylmorpholine (0.13ml) in methylene chloride (20 ml) was added dropwise isobutylchloroformate (0.31 ml) at -15° C. After 15 minutes, N-methylmorpholine(0.13 ml) and HCl·H-D-Glu(OBzl)-OPac (0.85 g) were added to thissolution at -30° C. After being stirred for 1 hour, the mixture waswashed with 0.5N hydrochloric acid (10 ml), water (10 ml) and 1M sodiumhydrogen carbonate (10 ml), dried over magnesium sulfate andconcentrated in vacuo. The residual solid was triturated with ethylether to give Boc-D-Trp(CHO)-D-Glu(OBzl)-OPac (1.31 g).

mp: 142-144° C.

Rf: 0.79 (chloroform:methanol=9:1).

PREPARATION 31-4)

Boc-D-Trp(CHO)-D-Phe-OPac was obtained in a similar manner to that ofPreparation 1-1).

mp: 142-146° C.

Rf: 0.78 (chloroform:methanol=9:1).

PREPARATION 31-5)

Boc-D-Trp(CHO)-OH (1.0 g), HCl·H-βAla-OPac (0.81 g), HOBT (0.49 g), WSCD(0.56 g) and DMF (10 ml) were reacted in a similar manner to that ofPreparation 1-1) to give Boc-D-Trp(CHO)-βAla-OPac (3.15 g).

mp: 153-155° C.

Rf: 0.58 (chloroform:methanol=9.1).

PREPARATION 31-6)

Boc-D-Trp(CHO)-OH (10.0 g), HCl·H-βAla-OMe (4.41 g) HOBt (4.47 g), WSCD(5.14 g) and DMF (100 ml) were reacted in a similar manner to that ofPreparation 1-1) to give Boc-D-Trp(CHO)-βAla-OMe (8.77 g).

mp: 134-135° C.

Rf: 0.54 (CHCl₃ :MeOH=9:1).

PREPARATION 31-7)

Boc-D-Phe-OH (265 mg), 2HCl·H-D-Pya-OEt (267 mg), HOBt (0.16 g) WSCD(0.19 g), N-methylmorpholine (0.10 g) and DMF (6 ml) were reacted in asimilar manner to that of Preparation 1-1) to give Boc-D-Phe-D-Pya-OEt(0.32 g).

mp: 97-99° C.

Rf: 0.58 (CHCl₃ :MeOH=9:1).

The following compounds could be obtained by removing t-butoxycarbonylgroups from the corresponding starting compounds in a similar manner tothat of Preparation 1-2).

PREPARATION 32-1)

HCl·H-D-Trp(Me)-D-Leu-OBzl

mp: 85-90° C.

Rf: 0.27 (CHCl₃ :MeOH=9:1).

PREPARATION 32-2)

2HClαN.sup.α -methyl-D-Trp(Me)-D-Pya-OEt

mp: 100-110° C.

Rf: 0.50 (CHCl₃ :MeOH=9:1).

PREPARATION 32-3)

2HCl·H-D-Trp(CHO)-D-Pya-OEt

Rf: 0.16 (CHCl₃ :MeOH:AcOH=8:1:1, V/V).

PREPARATION 32-4)

HCl·H-D-Trp(CHO)-D-Glu(OBzl)-OPac

mp: 80-89° C.

Rf=0.50 (chloroform:methanol=9:1).

PREPARATION 32-5)

HCl·H-D-Trp(CHO)-D-Phe-OPac

mp: 185° C. (dec.).

Rf: 0.37 (chloroform:methanol:acetic acid=16:1:1).

PREPARATION 32-6)

HCl·H-D-Trp(CHO)-βAla-OPac

mp: 157-164° C.

Rf: 0.17 (chloroform:methanol:acetic acid=16:1:1).

PREPARATION 32-7)

HCl·H-D-Trp(CHO)-βAla-OMe

mp: 168-169° C.

Rf: 0.53 (10% MeOH in CHCl₃).

PREPARATION 32-8)

2HCl·H-D-Phe-D-Pya-OEt

Rf: 0.12 (10% MeOH in CHCl₃).

The following compounds could be obtained by reacting(S)-α-benzyloxycarbonyl-γ-methylbutyl isocyanate with the correspondingamines in a similar manner to that of Preparation 7.

PREPARATION 33-1)

N-(Pyrrolidin-1-ylcarbonyl)-L-Leu-OBzl

Rf: 0.14 (EtOAc:hexane=1:2).

PREPARATION 33-2)

N-(Piperidin-1-ylcarbonyl)-L-Leu-OBzl

mp: 75-76° C.

Rf: 0.27 (EtOAc:hexane=1.2).

PREPARATION 33-3)

N-[(2S)-4-Methyl-2-(1-methylpropyl)-3-oxopiperidin-1-ylcarbonyl]-L-Leu-OBzl

Rf: 0.13 (EtOAc:hexane=1:1, V/V).

PREPARATION 33-4)

N-[{(1S)-1-(N,N-Dimethylcarbamoyl)-1-cyclohexylmethyl}carbamoyl]-L-Leu-OBzl

Rf: 0.26 (EtOAc:hexane=1:1, V/V).

PREPARATION 33-5)

N-[{(1S)-1-(N,N-Dimethylcarbamoyl)-1-phenylmethyl}-carbamoyl]-L-Leu-OBzl

Rf: 0.08 (EtOAc:hexane=1:2, V/V).

PREPARATION 33-6)

N-[{cis-4-(N,N-Dimethylcarbamoylmethyl)cyclohexyl}carbamoyl]-L-Leu-OBzl

Rf: 0.25 (ethyl acetate).

PREPARATION 33-7)

N-[{cis-4-(N,N-Dimethylcarbamoyl)cyclohexyl}carbamoyl]-L-Leu-OBzl

Rf: 0.34 (ethyl acetate).

PREPARATION 33-8)

N-(N,N-Dimethylcarbamoylmethyl)carbamoyl-L-Leu-OBzl

Rf: 0.23 (ethyl acetate).

PREPARATION 33-9)

N-[{2-(N,N-Dimethylcarbamoyl)ethyl}carbamoyl]-L-Leu-OBzl

Rf: 0.33 (ethyl acetate).

PREPARATION 33-10)

N-[(trans-4-Hydroxycyclohexyl)carbamoyl]-L-Leu-OBzl.

mp: 169-171° C.

Rf: 0.53 (ethyl acetate).

PREPARATION 3-11)

N-[{(1S)-1-(Hydroxymethyl)-3-methylbutyl}carbamoyl]L-Leu-OBzl

Rf: 0.38 (n-hexane:ethyl acetate=1:1).

PREPARATION 33-12)

N-[{2-(Morpholino)ethyl}carbamoyl]-L-Leu-OBzl

Rf: 0.46 (CHCl₃ :MeOH:AcOH=8:2:1).

PREPARATION 33-13)

N-(ε-Caprolactam-3-ylcarbamoyl)-L-Leu-OBzl

mp: 148 -150° C.

Rf=0.52 (ethyl acetate).

PREPARATION 33-14)

N-(N'-Isobutyrylhydrazinocarbonyl)-L-Leu-OBzl

mp: 93-96° C.

Rf: 0.16 (n-hexane:ethyl acetate=1:1).

PREPARATION 33-15 )

N-[(1-Ethoxycarbonylpiperidin-4-yl)carbamoyl]-L-Leu-OBzl

Rf: 0.35 (n-hexane:ethyl acetate=1:1).

The following compounds were obtained by removing benzyl groups from thecorresponding starting compounds in a similar manner to that ofPreparation 1-4).

PREPARATION 34-1)

N-(Pyrrolidin-1-ylcarbonyl)-L-Leu-OH

Rf: 0.18 (10% MeOH in CHCl₃).

PREPARATION 34-2)

N-(Piperidinocarbonyl)-L-Leu-OH

Rf: 0.17 (10% MeOH in CHCl₃).

PREPARATION 34-3)

N-(2-Chlorophenycarbamoyl)-L-Leu-OH

Rf: 0.20 (10% MeOH in CHCl₃).

PREPARATION 34-4)

N-(o-Chlorophenylacetyl)-L-Leu-OH

mp: 145-146° C.

Rf: 0.21 (10% MeOH in CHCl₃).

PREPARATION 34-5)

(2R)-2-[{(1S)-1-(N,N-Dimethylcarbamoyl)-2,2-dimethylpropyl}carbamoyl]methyl-4-methylvalericacid

Rf: 0.43 (10% MeOH in CHCl₃).

PREPARATION 34-6)

N-[(2S)-4-Methyl-2-(1-methylpropyl)-3-oxopiperazin-1-ylcarbonyl]-L-Leu-OH

mp: 180° C. (dec.).

Rf: 0.20 (10% MeOH in CHCl₃).

PREPARATION 34-7)

N-[{(1S)-1-(N,N-Dimethylcarbamoyl)-1-cyclohexylmethyl}carbamoyl]-L-Leu-OH

mp: 210-211° C.

Rf: 0.20 (10% MeOH in CHCl₃).

PREPARATION 34-8)

N-[{(1S)-1-(N,N-Dimethylcarbamoyl)-1-phenylmethyl}carbamoyl]-L-Leu-OH

Rf: 0.38 (CHCl₃ :MeOH:AcOH=16:1:1, V/V).

PREPARATION 34-9)

N-(Hexahydro-1H-azepin-1-ylcarbonyl)-N-methyl-Leu-OH

Rf: 0.58 (benzene:ethyl acetate:acetic acid=20:20:1, V/V).

PREPARATION 34-10)

N-[{cis-4-(N,N-Dimethylcarbamoylmethyl)cyclohexyl}carbamoyl]-L-Leu-OH

Rf: 0.57 (CHCl₃ :MeOH:AcOH=8:1:1).

PREPARATION 34-11)

N-[{cis-4-(N,N-Dimethylcarbamoyl)cyclohexyl}-carbamoyl]-L-Leu-OH

Rf: 0.52 (CHCl₃ :MeOH:AcOH=8:1:1).

PREPARATION 34-12)

N-(N,N-Dimethylcarbamoylmethyl)carbamoyl-L-Leu-OH

Rf: 0.73 (CHCl₃ :MeOH:AcOH=8:2:1).

PREPARATION 34-13)

N-[{2-(N,N-Dimethylcarbamoyl)ethyl}carbamoyl]-L-Leu-OH

Rf: 0.77 (CHCl₃ :MeOH:AcOH=8:2:1).

PREPARATION 34-14)

N-[(trans-4-Hydroxycyclohexyl)carbamoyl]-L-Leu-OH

Rf: 0.78 (CHCl₃ :MeOH:AcOH=8:1:1).

PREPARATION 34-15)

N-[N-(2-Hydroxyethyl)-N-methylcarbamoyl]-L-Leu-OH

Rf: 0.65 (CHCl₃ :MeOH:AcOH=8:1:1).

PREPARATION 34-16)

N-[{(1S)-(1-Hydroxymethyl)-3-methylbutyl}carbamoyl]-L-Leu-OH

Rf: 0.38 (benzene:ethyl acetate:acetic acid=20:20:1).

PREPARATION 34-17)

N-]{2-(Morpholino)ethyl}carbamoyl]-L-Leu-OH

Rf: 0.21 (CHCl₃ :MeOH:AcOH=8:2:1).

PREPARATION 34-18)

N-(ε-Caprolactam-3-ylcarbamoyl)-L-Leu-OH

Rf: 0.67 (CHCl₃ :MeOH:AcOH=8:2:1).

PREPARATION 34-19)

N-(N'-Isobutyrylhydrazinocarbonyl)-L-Leu-OH

Rf: 0.45 (CHCl₃ :MeOH:AcOH=8:1:1).

PREPARATION 34-20)

N-[(1-ethoxycarbonylpiperidin-4-yl)-carbamoyl]-L-Leu-OH

Rf: 0.48 (CHCl₃ :MeOH:AcOH=8:1:1).

PREPARATION 35

Hexahydro-1H-azepine (0.3 g),(S)-α-benzyloxycarbonyl-γ,γ-dimethylbutylisocyanate (0.48 g) and EtOAc(10 ml) were reacted in a similar manner to that of Preparation 7 togive N-(hexahydro-1H-azepin-1-ylcarbonyl)-γmethyl-L-Leu-OBzl. Thisproduct, 10% pd-C (60 mg), MeOH (10 ml) and H₂ O (1 ml) were reacted ina similar manner to that of Preparation 1-4) to giveN-(hexahydro-1H-azepin-1-ylcarbonyl)-γ-methyl-L-Leu-OH (0.43 g).

mp: 64-66° C.

Rf: 0.20 (10% MeOH in CHCl₃).

PREPARATION 36-1)

Boc-D-1-Nal-OH (0.50 g), methanesulfonamide (0.18 g) DMAP (0.23 g),WSCD·HCl (0.37 g) and CH₂ Cl₂ (10 ml) were reacted in a similar mannerto that of Preparation 1-1) to give Boc-D-1-Nal-methanesulfonamide (0.63g).

Rf: 0.48 (10% MeOH in CHCl₃).

PREPARATION 36-2)

Boc-D-Phe-OH (0.20 g), methanesulfonamide (79 mg) DMAP (0.11 g),WSCD·HCl (0.17 g) and DMF (4 ml) were reacted in a similar manner tothat of Preparation 1-1) to give Boc-D-Phe-methanesulfonamide (0.21 g).

mp: 73-75° C.

Rf: 0.80 (CHCl₃ :MeOH:AcOH=8:1:1, V/V).

PREPARATION 36-3)

Boc-D-Phe-OH (0.20 g), benzenesulfonamide (0.13 g), DMAP (0.11 g)WSCD·HCl (0.17 g) and CH₂ Cl₂ (4 ml) were reacted in a similar manner tothat of Preparation 1-1) to give Boc-D-Phe-benzenesulfonamide (0.32 g).

Rf: 0.83 (CHCl₃ :MeOH:AcOH=8:1:1, V/V).

PREPARATION 36-4)

Boc-D-Pya-OH (0.20 g), diethylamine (66 mg), HOBt (0.12 g), WSCD·HCl(0.17 g) and DMF (2 ml) were reacted in a similar manner to that ofPreparation 1-1) to give Boc-D-Pya-diethylamide (45 mg).

mp: 133-135° C.

Rf: 0.32 (EtOAc).

PREPARATION 37-1)

Boc-D-1-Nal-methanesulfonamide (0.60 g), 4N HCl-EtOAc (10 ml) and EtOAc(3 ml) were reacted in a similar manner to that of Preparation 1-2) togive HCl·H-D-1-Nal-methanesulfonamide.

mp: 250° C. (dec.).

Rf: 0.42 (CHCl₃ :MeOH AcOH=8:2:1, V/V).

PREPARATION 37-2)

Boc-D-Phe-methanesulfonamide (0.19 g) and 4N HCl-EtOAc (10 ml) werereacted in a similar manner to that of Preparation 1-2) to giveHCl·H-D-Phe-methanesulfonamide (0.13 g).

mp: 243° C. (dec.).

Rf: 0.12 (CHCl₃ :MeOH:AcOH=8:1:1, V/V).

PREPARATION 37-3)

Boc-D-Phe-benzenesulfonamide (0.30 g) and 4N HCl-EtOAc (10 ml}werereacted in a similar manner to that of Preparation 1-2) to giveHCl·H-D-Phe-benzenesulfonamide (0.22 g).

Rf: 0.22 (CHCl₃ :MeOH:AcOH=8:1:1, V/V).

mp: 230° C. (dec.).

PREPARATION 37-4)

Boc-D-Pya-diethylamide (45 mg) and 4N HCl-EtOAc (1 ml) were reacted in asimilar manner to that of Preparation 1-2) to give2HCl·H-D-Pya-diethylamide (41 mg).

Rf: 0.18 (10% MeOH in CHCl₃).

PREPARATION 38-1)

o-Chlorophenyl isocyanate (1.54 g), TosOH·H-L-Leu-OBzl (3.94 g)N-methylmorpholine (1.1 g) and EtOAc (50 ml) were reacted in a similarmanner to that of Preparation 7 to giveN-(2-chlorophenylcarbamoyl)-L-Leu-OBzl (4.30 g).

Rf: 0.86 (10% MeOH in CHCl₃).

PREPARATION 38-2)

o-Chlorophenylacetic acid (0.73 g), HCl·H-L-Leu-OBzl (1.0 g), WSCD (0.66g) and CH₂ Cl₂ (20 ml) were reacted in a similar manner to that ofPreparation 1-1) to give N-(o-chlorophenylacetyl)-L-Leu-OBzl.(1.4 g).

mp: 75-77° C.

Rf: 0.86 (10% MeOH in CHCl₃).

PREPARATION 39

To a stirring solution of N-Boc-N-methyl-glycinal (2.0 g) andHCl·H-L-Ile-OMe (2.0 g) in MeOH was added sodium cyanoborohydride (0.87g) at room temperature. After 30 minutes, the solvent was evaporated invacuo and the residue was dissolved in ethyl acetate (50 ml) and washedwith sodium hydrogen carbonate. The organic layer was dried overmagnesium sulfate and concentrated in vacuo. The residue was purified bya silica gel column chromatography (40 g, ethyl acetate:hexane=1:3˜3:1as an eluent) to give N-[2-(N-Boc-N-methylamino)ethyl]-L-Ile-OMe (1.67g).

Rf: 0.78 (EtOAc:hexane=2:1, V/V).

PREPARATION 40

N-[2-(N-Boc-N-methylamino)ethyl]-L-Ile-OMe (1.60 g) and 4N HCl-EtOAc (20ml) were reacted in a similar manner to that of Preparation 1-2) to give2HCl·N-[2-(Nmethylamino)ethyl]-L-Ile-OMe (1.40 g).

mp: 148-150° C.

Rf: 0.19 (10% MeOH in CHCl₃).

PREPARATION 41

2HCl·N-[2-(N-methylamino)ethyl]-L-Ile-OMe (1.30 g) was dissolved in 24NNH₃ -MeOH (20 ml) at room temperature and the solution was allowed tostand for 5 days. The solvent was evaporated in vacuo and the residuewas dissolved in EtOAc (30 ml) and washed with sodium hydrogen carbonate(20 ml). The organic layer was dried over magnesium sulfate andconcentrated in vacuo to give(3S)-1-methyl-3-(1-methylpropyl)-2-oxopiperazine (0.69 g).

Rf: 0.57 (10% MeOH in CHCl₃).

PREPARATION 42

To a stirring suspension of N.sup.α -Boc-N^(in) -methyl-D-Trp-OH (1.0 g)and NaH (0.31 g, 60% in oil) in tetrahydrofuran was added methyl iodide(1.34 g) at room temperature. After eight days, the mixture wasevaporated in vacuo and the residue was suspended in EtOAc (30 ml) andwashed with 1N HCl and brine. The organic layer was dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by silicagel column chromatography (20 g, 2% MeOH in CHC13 as an eluent) to giveN.sup.α_(-Boc-N).sup.α -methyl-N^(in) -methyl-D-Trp-OH (0.70 g).

Rf: 0.42 (10% MeOH in CHCl₃).

PREPARATION 43

Finely powdered potassium carbonate (5.8 g) was suspended in a solutionof 2-(aminomethyl)pyridine (3.0 g) and ethyl bromoacetate (3.1 ml) indimethylformamide (30 ml). The mixture was stirred at room temperatureovernight, then poured into ice water. The mixture was extracted withethyl acetate (50 ml×2) and the organic layer was washed with saturatedsodium chloride solution (2 times), dried over magnesium sulfate, andevaporated in vacuo. The residue was purified with a silica gel columnchromatography (MeOH:CHCl₃ =1:99 as an eluent) to giveN-(ethoxycarbonylmethyl)-N-(pyridin-2-ylmethyl)amine (2.30 g).

Rf: 0.27 (MeOH:CHCl₃ =1:19).

PREPARATION 44

A solution of 2-[2-(t-butoxycarbonylamino)ethyl]pyridine (2 g) indimethylformamide (10 ml) was added to a suspension of sodium hydride(0.54 g) in dimethylformamide (10 ml) at 0° C. The mixture was stirredat 0° C for 1 hour and at room temperature for 1 hour. Then a solutionof ethyl bromoacetate (1.5 ml) in dimethylformamide (5 ml) was addedthereto, and the mixture was stirred at room temperature for 2 hours.The solution was poured into saturated ammonium chloride (50 ml) and themixture was extracted with ethyl acetate (30 ml×2). The combined organiclayer was washed with saturated sodium chloride solution, dried overmagnesium sulfate, and evaporated in vacuo. The residue was purifiedwith silica gel column chromatography (MeOH:CHCl₃ =1:99 as an eluent) togive2-[2-{N-(t-butoxycarbonyl)-N-(ethoxycarbonylmethyl)amino}ethyl]pyridine.

Rf: 0.47 (CHCl₃ :MeOH=1:19).

PREPARATION 45

2-[2-{N-(t-Butoxycarbonyl)-N-(ethoxycarbonylmethyl)amino}ethyl]pyridine(439 mg) and 4NHCl-1,4-dioxane (5 ml) were reacted in a similar mannerto that of Preparation 1-2) to giveN-(ethoxycarbonylmethyl)-N-[2-(pyridin-2-yl)ethyl]amine dihydrochloride(400 mg).

Rf: 0.24 (MeOH:CHCl₃ =1:19).

PREPARATION 46

N-Methyl-L-Leu-OBzl hydrochloride (600 mg), trichloromethylchloroformate (0.54 ml), and hexamethyleneimine (877 mg) were reacted ina similar manner to those of Preparations 29-2) and 29-3) to giveN-(hexahydro-1H-azepin-1-ylcarbonyl)-N-methyl-L-Leu-OBzl (515 mg).

Rf: 0.44 (n-hexane:ethyl acetate=3:1).

PREPARATION 47

Boc-L-Asp(OBzl)-OH (1.0 g), 2-aminopyridine (0.35 g), HOBT (0.50 g),WSCD (0.71 g) and DMF (20 ml) were reacted in a similar manner to thatof Preparation 1-1) to give Boc-L-Asp(OBzl)-2-pyridylamide.

Rf: 0.52 (CHCl₃ :MeOH:AcOH=16:1:1).

PREPARATION 48

H-L-Asp(OBzl)-2-pyridylamide.2HCl was obtained in a similar manner tothat of Preparation 1-2).

mp: 170-178° C.

Rf: 0.23 (chloroform:methanol:acetic acid=8:1:1).

PREPARATION 49

HCl·H-L-tert-Leu dimethylamide (0.22 g), benzyl(2R)-2-(carboxymethyl)-4-methylvalerate (0.30 g), WSCD (0.21 g) and CH₂Cl₂ (8 ml) were reacted in a similar manner to that of Preparation 1-1)to give benzyl(2R)-2-[{(1S)-1-(N,N-dimethylcarbamoyl)-2,2-dimethylpropyl}carbamoyl]methyl-4-methylvalerate(0.40 g).

Rf: 0.71 (10% MeOH in CHCl₃).

EXAMPLE 1-1)

To a mixture of N-phenylacetyl-L-Leu-OH (0.25 g),HCl·H-D-Trp(CH₃)-D-Phe-OCH₃ (0 48 g) and HOBT (0.16 g) in DMF (8 ml) wasadded WSCD (0.19 g) under ice-bath cooling. After being stirred for 4.5hours at the same temperature, the mixture was concentrated in vacuo andthe residue was dissolved in ethyl acetate (50 ml). The solution waswashed with 0.5N HCl (10 ml), saturated aqueous sodium bicarbonate (10ml), and brine (10 ml) successively, dried over magnesium sulfate andconcentrated in vacuo. The residue was triturated with ether to give theobject compound (0.90 g).

mp: 185-188° C.

Rf: 0.52 (CHCl₃ :MeOH=9:1).

EXAMPLE 1-2)

To a solution of N-phenylacetyl-L-Leu-D-Trp(CH3)-D-Phe-OCH₃ (0.85 g) inDMF (7 ml) was added 1N NaOH (1.5 ml) at 0° C. After being stirred for20 minutes at the same temperature, the mixture was acidified with 1NHCl (2 ml) and concentrated in vacuo. The residue was dissolved in ethylacetate (20 ml) and the solution was washed with 0.5N HCl (10 ml) andbrine (10 ml). The organic layer was dried over magnesium sulfate andconcentrated in vacuo. The residue was triturated with ether to give theobject compound (0.50 g).

mp: 177-185° C.

FAB-MS m/z: 598 [M+H]⁺.

Rf: 0.52 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 2-1)

3-Phenylpropionic acid (33 mg), HCl·H-L-Leu-D-Trp(CH₃)-D-Phe-OBzl (0.12g), HOBT (32 mg) and WSCD (37 mg) in DMF (2 ml) were reacted in asimilar manner to that of Example 1-1) to give the object compound (0.13g).

mp: 218-220° C.

Rf: 0.74 (CHCl₃ MeOH=9:1).

EXAMPLE 2-2)

N-(3-Phenylpropionyl)-L-Leu-D-Trp(CH3)-D-Phe-OBzl (0.1 g) in DMF (1.5ml) was hydrolyzed with 1N NaOH (0.5 ml) in a similar manner to that ofExample 1-2) to give the object compound (68 mg).

mp: 175-180° C.,

Rf: 0.51 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z:611 [M+H]⁺.

EXAMPLE 3-1)

Cyclohexylacetic acid (31 mg), HCl·H-L-Leu-D-Trp(CH₃)-D-Phe-OBzl (0.12g), HOBT (32 mg) and WSCD (37 mg) in DMF (2 ml) was reacted in a similarmanner to that of Example 1-1) to give the object compound (0.12 g).

mp: 191-194° C.

Rf: 0.74 (CHCl₃ :MeOH=9:1).

EXAMPLE 3-2)

N-Cyclohexylacetyl-L-Leu-D-Trp(CH₃)-D-Phe-OC₂ H₅ (0.1 g) was reactedwith 1N NaOH (0.5 ml) in DMF (1.5 ml) in a similar manner to that ofExample 1-2) to give the object compound (63 mg).

mp: 225-228° C.

Rf: 0.51 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 603 [M+H]⁺.

EXAMPLE 4-1)

To a solution of HCl·H-L-Leu-D-Trp(CH₃)-D-Phe-OBzl 120 mg) and Et₃ N (22mg) in DMF (5 ml) was added phenyl isocyanate (26 mg) at roomtemperature. The mixture was stirred at the same temperature for 30minutes. After evaporation of the solvent, the residue was dissolved inAcOEt (20 ml) and the solution was washed with 5% HCl, 1M aqueous sodiumbicarbonate and saturated aqueous sodium chloride solution successively,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was crystallized from ether to give the objectcompound (115 mg).

mp: 222-224° C.

Rf: 0.77 (CHCl₃ :MeOH=9:1).

EXAMPLE 4-2)

N-Phenylcarbamoyl-L-Leu-D-Trp(CH₃)-D-Phe-OBzl (115 mg) in DMF (2 ml) washydrolyzed with 1N NaOH (0.3 ml) in a similar manner to that of Example1-2) to give the object compound (93 mg).

mp: 248-251° C.

Rf: 0.60 (CHCl₃ MeOH:AcOH=16:1:1).

EXAMPLE 5-1)

HCl·H-L-Leu-D-Trp(CH₃)-D-Phe-OBzl (300 mg), Et₃ N (50.2 mg) andcyclohexyl isocyanate (68.2 mg) in DMF (10 ml) was reacted at roomtemperature for 30 minutes in a similar manner to that of Example 4-1)to give the object compound (325 mg).

mp: 218-220° C.

Rf: 0.67 (CHCl₃ :MeOH=9:1).

EXAMPLE 5-2)

N-Cyclohexylcarbamoyl-L-Leu-D-Trp(CH₃)-D-Phe-OBzl (300 mg) in DMF (10ml) was hydrolyzed with 1N NaOH (2.2 ml) at room temperature for 30minutes in a similar manner to that of Example 1-2) to give the objectcompound (246 mg).

mp: 219-221° C.

Rf: 0.52 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 6-1)

N-Phenylacetyl-L-Leu-D-Trp(CH₃)-OH (0.20 g), HOBT (72 mg), WSCD (83 mg)and NMM (54 mg) were reacted in a similar manner to that of Preparation3-3) to give the object compound (0.21 g).

mp: 130-137° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

FAB-MS m/z: 626 [M+H]⁺.

EXAMPLE 6-2)

N-Phenylacetyl-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅ ·HCl (0.15 g) in DMF (2 ml)was reacted with 1N-NaOH (1 ml) at 0° C. for 20 minutes in a similarmanner to that of Example 1-2) to give the object compound (102 mg).

mp: 205° C. (dec.).

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:1:1).

FAB-MS m/z: 598 [M+H]⁺.

EXAMPLE 7-1)

2HCl·H-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅ (350 mg), Et₃ N (122 mg) andcyclohexyl isocyanate (91 mg) in DMF (10 ml) was reacted at roomtemperature for 30 minutes in a similar manner to that of Example 4-1)to give the object compound (284 mg).

mp: 216-218° C.

Rf: 0.61 (CHCl₃ :MeOH=9:1).

EXAMPLE 7-2)

N-Cyclohexylcarbamoyl-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅ (230 mg) in MeOH (10ml) was reacted with 1N NaOH (1.6 ml) at room temperature for 1 hour ina similar manner to that of Example 1-2) to give the object compound(125 mg).

mp: 207-210° C.

Rf: 0.45 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 8-1)

N-Phenylacetyl-L-Leu-D-Trp(CH₃)-OH (90 mg), HCl·H-L-Phe-OEt (46 mg),WSCD (33 mg) and HOBT (27 mg) in DMF (2 ml) was reacted at 5° C.overnight in a similar manner to that of Example 1-1) to give the objectcompound (87 mg).

Rf: 0.38 (CHCl₃ :AcOEt=3:1).

EXAMPLE 8-2)

N-Phenylacetyl-L-Leu-D-Trp(CH₃)-L-Phe-OEt (64 mg) in DMSO (2 ml) wasreacted with 1N NaOH (0.2 ml) at room temperature for 2 hours in asimilar manner to that of Example 1-2) to give the object compound (48mg).

mp: 172-175° C.

Rf: 0.30 (CHCl₃ MeOH=5:1).

EXAMPLE 9

To a solution of N-cyclohexylcarbamoyl-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅(920 mg) in DMF (20 ml) was added 1N NaOH (7.3 ml) at room temperature.After 10 minutes, 1N HCl (8.5 ml) was added and the solution wasevaporated in vacuo. The residue was dissolved in 1N HCl (50 ml) andwater (200 ml), and applied to a column of "Diaion HP-20" (trademark,made by Mitsubishi Chemical Industries) eluting with MeOH (300 ml).After the eluate was concentrated in vacuo, the residue (750 mg) wasdissolved in 1N NaOH (1.24 ml) and lyophilized to give the objectcompound as a white powder (728 mg).

Rf: 0.45 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 10

N-[(1S)-2,2-Dimethyl-1-(N,N-dimethylcarbamoyl)propyl]carbamoyl-L-Leu-OH(0.28 g), H-D-Trp(CH3)-D-Pya-OC₂ H₅ ·2HCl (0.41 g), HOBT (0.14 g), WSCD(0.16 g) and TEA (89 mg) were reacted in DMF (7 ml) in a similar mannerto that of Example 1-1) to give the object compound (0.40 g).

mp: 141-145° C.

Rf: 0.43 (CHCl₃ :MeOH=9:1).

NMR (CDCl₃, δ): 0.82 (3H, d, J=6.0 Hz), 0.87 (3H, d J=6.0 Hz), 1.15 (3H,t, J=6.0 Hz), 1.35 (2H, t, J=6.0 Hz), 1.65 (1H, m), 2.58 (3H, s), 3.06(3H, s), 3.1-3.3 (4H, m), 3.70 (3H, s), 4.06 (2H, q, J=6.0 Hz), 4.34(1H, q, J=6.0 Hz), 4.75 (1H, d, J=10.0 Hz), 4.90 (1H, q, J=6.0 Hz), 5.13(1H, q, J=6.0 Hz), 6.20 (1H, d, J=10.0 Hz), 6.48 (1H, d, J=8.0 Hz), 6.58(1H, d, J=7.5 Hz), 6.90 (1H, s), 6.95-7.30 (6H, m), 7.56 (1H, td, J=7.5,2.0 Hz), 7.65 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=8.0 Hz), 8.34 (1H, d,J=5.0 Hz).

EXAMPLE 11

(2S)-2-[N-[(1S)-2,2-Dimethyl-1-(N,N-dimethylcarbamoyl)propyl]carbamoyloxy]-4-methylvalericacid (0.15 g), H-D-Trp(CH₃)-D-Pya-OC₂ H₅ ·2HCl (0.24 g), HOBT (77 mg),WSCD (88 mg) and NMM (53 mg) were reacted in DMF (4 ml) in a similarmanner to that of Example 1-1) to give the object compound (0.33 g).

Rf: 0.73 (CHCl₃ :MeOH=9:1).

EXAMPLE 12

N-(Hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-OH (1.51 g),2HCl·H-D-Trp(CH₃)-D-Pya-OC₂ H₅ (2.50 g), WSCD (997 mg), HOBT (868 mg)and NMM (541 mg) were reacted in DMF (60 ml) in a similar manner to thatof Example 1-1) to give the object compound (2.16 g).

Rf: 0.34 (ethyl acetate).

NMR (CDCl₃, δ): 0.82 (3H, d, J=6.0 Hz), 0.84 (3H, d, J=6.0 Hz), 1.18(3H, t, J=7.5 Hz), 1.3-1.8 (11H, m), 3.1-3.5 (7H, m), 3.68 (3H, s), 4.10(2H, q,

J=7.5 Hz), 4.10 (1H, br), 4.7-4.9 (3H, m), 6.68

(1H, d, J=8.0 Hz), 6.95 (1H, s), 7.0-7.3 (5H, m),

7.5 (1H, td, J=8.0, 2.0 Hz), 7.64 (2H, t,

J=8.0 Hz), 8.28 (1H, d, J=5.0 Hz).

EXAMPLE 13

(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonylmethyl)-4-methylvaleric acid(982 mg). 2HCl·H-D-Trp(CH3)-D-Pya-OC₂ (1.54 g), WSCD (612 mg), HOBT (532mg) and TEA (332 mg) were reacted in DMF (30 ml) in a similar manner tothat of Example 1-1) to give the object compound (1.41 g).

Rf: 0.43 (CHCl₃ :MeOH=9:1).

EXAMPLE 14

N-(Octahydroazocin-1-ylcarbonyl)-L-Leu-OH (191 mg),2HCl·H-D-Trp(CH₃)-D-PYa-OC₂ H₅ (300 mg), WSCD (120 mg), HOBT (104 mg)and TEA (65 mg) were reacted in DMF (20 ml) in a similar manner to thatof Example 1-1) to give the object compound (340 mg).

Rf: 0.60 (CHCl₃ :MeOH=9:1).

EXAMPLE 15

2HCl·H-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅ (4.35 g),hexahydro-1H-azepin-1-ylcarbonyl chloride (1.29 g) and TEA (2.33 g) werereacted in DMF (60 ml) in a similar manner to that of Example 4-1) togive the object compound (1.95 g).

Rf: 0.44 (CHCl₃ :MeOH=9:1).

EXAMPLE 16

To a solution ofN-(hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅ (37g) in ethanol (740 ml) was added 1N NaOH (146 ml) under ice-bathcooling. After stirring for 30 minutes, 1N HCl (150 ml) was added to thereaction mixture, and the solvent was removed by evaporation in vacuo.The residue was dissolved in 1N HCl (500 ml) and water (5000 ml) andapplied to a column chromatography using non-ionic adsorption resin"Diaion HP-20" (3 l), which was eluted with methanol (10 l). After theeluent was concentrated in vacuo, the residue was crystallized fromn-hexane to give the object compound (34.1 g).

mp: 113-118° C.

Rf: 0.34 (CHCl₃ :MeOH:AcOH=8:1:1).

NMR (CDCl₃, δ): 0.89 (6H, d, J=5.0 Hz), 1.32-1.80 (11H, m), 3.11 (2H, d,J=6.0 Hz), 3.16-3.53 (6H, m), 3.78 (3H, x), 4.20 (1H, br), 4.22-4.48(1H, m), 4.59 (1H, q, J=6.0 Hz), 4.77 (1H, q, J=7.0 Hz), 4.90 (1H, d,J=7.5 Hz), 7.01 (1H, s), 7.04-7.52 (7H, m), 7.71 (1H, d, J=7.0 Hz), 7.82(1H, t, J=8.0 Hz), 8.48 (1H, d, J=5.0 Hz).

EXAMPLE 17

N-(Hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅ (1.35g and 1N NaOH (6.4 ml) were reacted in ethanol (30 ml) in a similarmanner to that of Example 9 to give the object compound (1.08 g).

Rf: 0.44 (CHCl₃ :MeOH:AcOH=8:1:1).

NMR (DMSO-d₆, δ): 0.74 (3H, d, J=3.0 Hz), 0.79 (3H, d, J=3.0 Hz),1.08-1.67 (11H, m), 2.72-3.12 (3H, m), 3.18-3.38 (5H, m), 3.69 (3H, s),4.09-4.25 (2H, m), 4.28-4.43 (1H, m), 6.08 (1H, d, J=8.5 Hz), 6.92-7.15(4H, m), 7.25 (1H, d, J=8.0 Hz), 7.32 (1H, d, J=8.0 Hz), 7.49-7.62 (2H,m), 7.69 (1H, d, J=8.5 Hz), 8.03 (1H, d, J=9.0 Hz), 8.40 (1H, d, J=4.0Hz).

EXAMPLE 18

N-[N-[(1S)-2,2-Dimethyl-1-(N,N-dimethylcarbamoyl)propyl]carbamoyl]-L-Leu-D-Trp(CH₃)-D-Pya-OC₂H₅ (0.31 g) and 1N NaOH (1.5 ml) were reacted in DMF in a similar mannerto that of Example 9 to give the object compound (0.25 g).

Rf: 0.31 (CHCl₃ :MeOH:AcOH=8:1:1).

NMR (DMSO-d₆, δ): 0.66 (6H, d, J=6.0 Hz), 0.88 (9H, s), 1.0-1.3 (3H, m),2.7-3.3 (4H, m), 2.8 (3H, s), 3.08 (3H, s), 3.68 (3H, s), 4.08 (1H, q,J=6.0 Hz), 4.20 (1H, q, J=5.0 Hz), 4.38 (1H, m), 4.50 (1H, d, J=9.0 Hz),6.37 (1H, d, J=9.0 Hz), 6.48 (1H, d, J=7.5 Hz), 6.9-7.15 (4H, m), 7.2(1H, d, J=7.5 Hz), 7.3 (1H, d, J=7.5 Hz), 7.45-7.6 (2H, m), 7.66 (1H, d,J=7.5 Hz), 8.28 (1H, d, J=8.0 Hz), 8.38 (1H, d, J=4.0 Hz).

EXAMPLE 19

N-[(2S)-2-[N-[(1S)-2,2-dimethyl-1-(N,N-dimethylcarbamoyl)propyl]carbamoyloxy]-4-methylvaleryl]-D-Trp(CH₃)-D-Pya-OC₂H₅ (0.30 g) and 1N NaOH (1.3 ml) were reacted in DMF (2.6 ml) in asimilar manner to that of Example 9 to give the object compound (0.26g).

Rf: 0.20 (CHCl₃ :MeOH:AcOH=8:1:1).

NMR (DMSO-d₆, δ): 0.78 (6H, d, J=6.5 Hz), 0.88 (9H, s), 1.2-1.6 (3H, m),2.7-3.4 (4H, m), 2.83 (3H, s), 3.05 (3H, s), 3.66 (3H, s), 4.16 (1H, q,J=6.0 Hz), 4.34-4.48 (2H, m), 4.75 (1H, q, J=3.0 Hz), 6.9-7.7 (10H, m),8.16 (1H, d, J=10.0 Hz), 8.40 (1H, d, J=4.0 Hz).

EXAMPLE 20

N-[(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonylmethyl)-4-methylvaleryl]-D-Trp(CH₃)-D-Pya-OC₂H₅ (1.10 g) and 1N NaOH (5.2 ml) were reacted in ethanol (20 ml) in asimilar manner to that of Example 9 to give the object compound (783mg).

Rf: 0.49 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 21

N-(Octahydroazocin-1-ylcarbonyl)-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅ (300 mg)and 1N NaOH (2.4 ml) were reacted in ethanol (10 ml) in a similar mannerto that of Example 9 to give the object compound (210 mg).

Rf: 0.68 (CHCl₃ :MeOH:AcOH=8:2:1).

NMR (DMSO-d₆, δ): 0.75 (6H, d, J=5.5 Hz), 1.02-1.65 (16H, m), 2.72-3.32(5H, m), 3.68 (3H, s), 4.08-4.26 (2H, m), 4.29-4.45 (1H, m), 5.93 (1H,d, J=8.5 Hz), 6.92-7.18 (4H, m), 7.13 (1H, d J=8.0 Hz), 7.32 (1H, d,J=9.0 Hz), 7.48-7.69 (3H, m), 7.97 (1H, d, J=9.0 Hz), 8.38 (1H, d, J=4.5Hz).

EXAMPLE 22

To a solution ofN-(hexahydro-1H-azepin-1-ylcarbonyl-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅ (800mg) in ethanol (10 ml) was added 4N hydrogen chloride in ethyl acetatesolution (0.63 ml) under ice-bath cooling. After stirring for 5 minutesat the same temperature, the solution was concentrated in vacuo to givethe object compound (828 mg).

Rf: 0.64 (CHCl₃ :MeOH=9:1).

NMR (DMSO-d₆, δ): 0.71 (3H, d, J=5.0 Hz), 0.77 (3H, d, J=5.0 Hz), 1.14(3H, t, J=6.0 Hz), 1.15-1.66 (11H, m), 2.82 (1HJ, q, J=11.0 Hz),3.08-4.18 (8H, m), 3.72 (3H, s), 4.08 (2H, q, J=7.5 Hz), 4.32-4.48 (1H,m), 4.63-4.80 (1H, m), 6.13 (1H, br), 7.02 (2H, t, J=7.0 Hz), 7.13 (1H,t, J=7.5 Hz), 7.37 (1H, d, J=8.0 Hz), 7.57 (1H, d, J=7.5 Hz), 7.82 (2H,t, J=7.0 Hz), 8.22-8.42 (2H, m), 8.78 (2H, d, J=5.0 Hz).

EXAMPLE 23

N-[(2R)-2-hexahydro-1H,azepin-1-ylcarbonylmethyl)-4-methylvaleryl]-D-Trp(CH₃)-D-Pya-OC₂ H₅ (300ml) were reacted in ethanol (10 ml) in a similar manner to that ofExample 22 to give the object compound (298 mg).

Rf: 0.43 (CHCl₃ :MeOH=9:1).

The object compounds in Examples 24 to 71 could be obtained by reactingthe corresponding starting compounds (II) and (III) in a similar mannerto that of Example 1-1).

The physico chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 24

mp: 193-195° C.

Rf: 0.49 (CHCl₃ :MeOH=9:1).

EXAMPLE 25

mp: 186-189° C.

Rf: 0.62 (CHCl₃ :MeOH=9:1).

EXAMPLE 26

mp: 181-183° C.

Rf: 0.56 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 27

Rf: 0.49 (CHCl₃ :MeOH=9:1).

EXAMPLE 28

Rf: 0.77 (CHCl₃ :MeOH=9:1).

EXAMPLE 29

Rf: 0.77 (CHCl₃ :MeOH=9:1).

EXAMPLE 30

Rf: 0.57 (CHCl₃ :MeOH=9:1).

EXAMPLE 31

Rf: 0.56 (CHCl₃ :MeOH=9:1).

EXAMPLE 32

mp: 184-185° C.

Rf: 0.54 (CHCl₃ :MeOH=9:1).

EXAMPLE 33

Rf: 0.77 (CHCl₃ :MeOH=9:1).

EXAMPLE 34

Rf: 0.43 (CHCl₃ :MeOH=9:1).

EXAMPLE 35

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 36

Rf: 0.36 (CHCl₃ :MeOH=9:1).

EXAMPLE 37

mp: 79-81° C.

Rf: 0.60 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 38

mp: 69-71° C.

Rf: 0.43 (CHCl₃ :MeOH=9:1).

EXAMPLE 39

mp: 54-55° C.

Rf: 0.41 (CHCl₃ :MeOH=9:1).

EXAMPLE 40

mp: 100-105° C.

Rf: 0.41 (CHCl₃ :MeOH=9:1).

EXAMPLE 41

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 42

Rf: 0.55 (CHCl₃ :MeOH=9:1).

EXAMPLE 43

mp: 62-68° C.

Rf: 0.52 (CHCl₃ :MeOH=9:1).

EXAMPLE 44

mp: 60-67° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 45

mp: 70-75° C.

Rf: 0.58 (CHCl₃ :MeOH=9:1).

EXAMPLE 46

mp: 80-83° C.

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 47

Rf: 0.55 (CHCl₃ :MeOH=9:1).

EXAMPLE 48

Rf: 0.48 (CHCl₃ :MeOH=9:1).

EXAMPLE 49

mp: 140-142° C.

Rf: 0.43 (CHCl₃ :MeOH=9:1).

EXAMPLE 50

Rf: 0.52 (CHCl₃ :MeOH=9:1).

EXAMPLE 51

mp: 135-138° C.

Rf: 0.31 (CHCl₃ :MeOH=9:1).

EXAMPLE 52

mp: 190-193° C.

Rf: 0.70 (CHCl₃ :MeOH=9:1).

EXAMPLE 53

mp: 185-188° C.

Rf: 0.50 (CHCl₃ :MeOH=9:1).

EXAMPLE 54

mp: 170-178° C.

Rf: 0.48 (CHCl₃ :MeOH=9:1).

EXAMPLE 55

mp: 194-196° C.

Rf: 0.45 (CHCl₃ :MeOH=9:1).

EXAMPLE 56

mp: 166-167° C.

Rf: 0.70 (CHCl₃ :MeOH=9:1).

EXAMPLE 57

mp: 110-115° C.

Rf: 0.59 (CHCl₃ :MeOH=9:1).

EXAMPLE 58

mp: 79-80° C.

Rf: 0.79 (CHCl₃ :MeOH=9:1).

EXAMPLE 59

mp: 77-79° C.

Rf: 0.52 (CHCl₃ :MeOH=9:1).

EXAMPLE 60

Rf: 0.36 (CHCl₃ :MeOH=9:1).

EXAMPLE 61

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 62

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 63

mp: 184-188° C.

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 64

mp: 170-175° C.

Rf: 0.58 (CHCl₃ :MeOH=9:1).

EXAMPLE 65

Rf: 0.71 (CHCl₃ :MeOH=9:1).

EXAMPLE 66

mp: 183-190° C.

Rf: 0.60 (CHCl₃ :MeOH=9:1).

EXAMPLE 67

Rf: 0.70 (CHCl₃ :MeOH=9:1).

EXAMPLE 68

Rf: 0.79 (CHCl₃ :MeOH=9:1).

EXAMPLE 69

mp: 159-161° C.

Rf: 0.62 (CHCl₃ :MeOH=9:1).

EXAMPLE 70

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 71

mp: 148-150° C.

Rf: 0.78 (CHCl₃ :MeOH=9:1).

EXAMPLE 72

To a solution of HCl·H-L-Ile-OMe (135 mg) and Et₃ N (50.2 mg) in drytoluene (10 ml) was added trichloromethyl chloroformate (0.055 ml).After the solution was refluxed for 30 minutes, it was concentratedunder reduced pressure. The resulting residue was dissolved in DMF (10ml) and a mixture of HCl·H-L-Leu-D-Trp(CH₃)-D-Phe-OBzl (300 mg) and Et₃N (50.2 mg) in DMF (10 ml) was added to the solution at roomtemperature. After the reaction mixture was stirred for 1 hour, thesolvent was removed in vacuo. The resulting residue was dissolved inethyl acetate (30 ml) and the solution was washed with 5% HCl, 1M sodiumbicarbonate and saturated sodium chloride solution successively, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was crystallized from ether to give the objectcompound (324 mg).

mp: 184-186° C.

Rf: 0.80 (CHCl₃ :MeOH=9:1).

EXAMPLE 73

To a mixture of HCl·H-L-Leu-D-Trp(CH₃)-D-Phe-OBzl (0.12 g),4-pyridlyacetic acid (38 mg) and NMM (24 mg) in DMF (2 ml) was addedWSCD (37 mg) under ice-bath cooling. After being stirred for 3 hours atroom temperature, the mixture was concentrated in vacuo and the residuewas dissolved in ethyl acetate. The solution was washed with 0.5 N HCl,water, saturated sodium bicarbonate and water successively, dried overmagnesium sulfate and evaporated in vacuo. The residue was trituratedwith ether to give the object compound (107 mg).

mp: 122-125° C.

Rf: 0.46 (CHCl₃ :MeOH=9:1).

The object compounds in Examples 74 to 82 could be obtained by reactingthe corresponding starting compounds (I-a) and (IV) in a similar mannerto that of Example 73.

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 74

mp: 105-110° C.

Rf: 0.50 (CHCl₃ :MeOH=9:1).

EXAMPLE 75

mp: 98-108° C.

Rf: 0.65 (CHCl₃ :MeOH=9:1).

EXAMPLE 76

mp: 173-175° C.

Rf: 0.84 (CHCl₃ :MeOH=9:1).

EXAMPLE 77

mp: 196-199° C.

Rf: 0.79 (CHCl₃ :MeOH=9:1).

EXAMPLE 78

mp: 139-141° C.

Rf: 0.60 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 79

mp: 90-96° C.

Rf: 0.36 (CHCl₃ :MeOH=9:1).

EXAMPLE 80

mp: 206-209° C.

Rf: 0.45 (CHCl₃ :MeOH=9:1).

EXAMPLE 81

mp: 124-128° C.

Rf: 0.56 (CHCl₃ :MeOH=9:1).

EXAMPLE 82

Rf: 0.64 (CHCl₃ :MeOH=9:1).

EXAMPLE 83

To a mixture of benzylsulfonyl chloride (0.18 g) andHCl·H-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅ (0.50 g) in DMF (10 ml) was addedEt₃ N (0.42 ml) at 0° C.. After the reaction was completed, the solutionwas evaporated to dryness in vacuo. The residue was dissolved in ethylacetate, and the solution was washed with 0.5N HCl, dried over magnesiumsulfate and concentrated in vacuo. The residual solid was trituratedwith ether to give the object compound (0.29 g).

mp: 98-100° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 84

Morpholinocarbonyl chloride (108 mg) 2HCl·H-L-Leu-D-Trp(CH₃)-D-Pya-OC₂H₅ (350 mg) and Et₃ N (122 mg) were reacted in a similar manner to thatof Example 83 to give the object compound.

Rf: 0.45 (CHCl₃ :MeOH=9:1).

The object compounds in Examples 85 to 91 could be obtained by reactingthe corresponding starting compound (I-a) with the isocyanate compound(IV) in a similar manner to that of Example 4-1).

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 85

mp: 222-223° C.

Rf: 0.79 (CHCl₃ :MeOH=9:1).

EXAMPLE 86

mp: 198-204° C.

Rf: 0.49 (CHCl₃ :MeOH=9:1).

EXAMPLE 87

mp: 205-206° C.

Rf: 0.46 (CHCl₃ :MeOH=9:1).

EXAMPLE 88

mp: 216-218° C.

Rf: 0.45 (CHCl₃ :MeOH=9:1).

EXAMPLE 89

mp: 188-202° C.

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 90

mp: 167-172° C.

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 91

mp: 163-167° C.

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 92

To a mixture of N-cyclohexylcarbamoyl-L-Leu-D-Trp(CH₃)-OH (0.40 g),H-D-4Pya-OC₂ H₅ ·2HCl (0.26 g), NMM (0.10 g) and HOBT (0.14 g) in DMF (8ml) was added WSCD (0.16 g) under ice-bath cooling. After being stirredat room temperature, the mixture was concentrated in vacuo and theresidue was dissolved in ethyl acetate. The solution was washed with0.5N HCl, water, saturated sodium bicarbonate and water successively,dried over magnesium sulfate and evaporated in vacuo. The residue wastriturated with ether to give the object compound (0.45 g).

mp: 182-186° C.

Rf: 0.32 (CHCl₃ :MeOH:AcOH=16:1:1).

The object compounds in Examples 93 to 98 could be obtained by reactingthe corresponding starting compounds (V) and (VI) in a similar manner tothat of Example 92.

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 93

mp: 170-173° C.

Rf: 0.43 (CHCl₃ :MeOH=9:1).

EXAMPLE 94

mp: 181-182° C.

Rf: 0.71 (CHCl₃ :MeOH=9:1).

EXAMPLE 95

mp: 197-198° C.

Rf: 0.70 (CHCl₃ :MeOH=9:1).

EXAMPLE 96

mp: 115-123° C.

Rf: 0.74 (CHCl₃ :MeOH=9:1).

EXAMPLE 97

mp: 148-156° C.

Rf: 0.52 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 98

mp: 154-158° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

The object compounds in Examples 99 to 145 could be obtained byhydrolyzing the corresponding ethyl ester compound (I-c) with an aqueousNaOH in a similar manner to that of Example 1-2), 9 or 16.

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 99

mp: 167-170° C.

Rf: 0.44 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 100

mp: 173-178° C.

Rf: 0.62 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 101

mp: 150-155° C.

Rf: 0.25 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 102

Rf: 0.51 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 103

Rf: 0.69 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 104

Rf: 0.66 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 105

Rf: 0.78 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 106

Rf: 0.57 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 107

Rf: 0.52 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 108

Rf: 0.72 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 109

Rf: 0.56 (CHCl₃ :MeOH:AcOH=20:20:1).

EXAMPLE 110

Rf: 0.32 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 111

Rf: 0.31 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 112

mp: 150-155° C.

Rf: 0.29 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 113

Rf: 0.31 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 114

Rf: 0.31 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 115

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 116

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 117

Rf: 0.34 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 118

Rf: 0.32 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 119

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 120

Rf: 0.38 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 121

Rf: 0.34 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 122

Rf: 0.35 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 123

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 124

Rf: 0.31 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 125

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 126

Rf: 0.28 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 127

Rf: 0.30 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 128

Rf: 0.32 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 129

Rf: 0.29 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 130

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 131

Rf: 0.29 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 132

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 133

Rf: 0.31 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 134

Rf: 0.37 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 135

Rf: 0.46 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 136

Rf: 0.24 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 137

Rf: 0.38 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 138

Rf: 0.29 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 139

Rf: 0.32 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 140

Rf: 0.31 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 141

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 142

Rf: 0.53 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 143

Rf: 0.57 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 144

Rf: 0.50 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 145

Rf: 0.62 (CHCl₃ :MeOH:AcOH=8:1:1).

NMR (DMSO-d₆, δ): 0.54 (3H, d, J=6.0 Hz), 0.64 (3H, d, J=6.0 Hz), 0.72(-1.02 (2H, m), 1.10-1.72 (13H, m), 2.22-2.32 (1H, m), 2.55-2.82 (2H,m), 2.93-3.60 (6H, m), 3.68 (3H, s), 4.04-4.10 (1H, m), 4.24-4.40 (1H,m), 6.94-7.18 (4H, m), 7.20-7.42 (2H, m), 7.46-7.68 (3H, m), 8.30 (1H,d, J=7.5 Hz), 8.41 (1H, d, J=4.0 Hz).

The object compounds in Examples 146 to 151 could be obtained byhydrolyzing the corresponding benzyl ester compound (I-c) with anaqueous NaOH in a similar manner to that of Example 1-2), 9 or 16.

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 146

mp: 120-124° C.

Rf: 0.85 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 147

mp: 220-236° C.

Rf: 0.16 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB MS m/z: 598 [M+H]⁺.

EXAMPLE 148

mp: 214-218° C.

Rf: 0.20 (CHCl₃ :MeOH:AcOH:16:1:1).

FAB MS m/z: 598 [M+H]⁺.

EXAMPLE 149

mp: 174-180° C.

Rf: 0.32 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB MS m/z: 598 [M+H]⁺.

EXAMPLE 150

mp: 194° C. (dec.).

Rf: 0.51 (CHCl₃ :McOH:AcOH=16:1:1).

FAB MS m/z: 711 [M+H]⁺.

EXAMPLE 151

mp: 195° C. (dec.).

Rf: 0.51 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB MS m/z: 711 [M+H]⁺.

The object compounds in Examples 152 to 157 could be obtained byhydrolyzing the corresponding ethyl ester compound (I-c) with an aqueousNaOH in a similar manner to that of Example 1-2), 9 or 16.

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 152

mp: 127-145° C.

Rf: 0.29 (CHCl₃ :MeOH:AcOH=8:2:1).

FAB MS m/z: 672 [M+H]⁺.

EXAMPLE 153

Rf: 0.36 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 154

Rf: 0.38 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 155

Rf: 0.35 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 156

Rf: 0.32 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 157

Rf: 0.45 (CHCl₃ :MeOH:AcOH=8:1:1).

Isopropylcarbamoyl-L-Leu-D-Trp(CH₃)-D-Phe-OBzl (60 mg) was reacted with1N NaOH (2 ml) in DMF (2 ml) at room temperature for 30 minutes in asimilar manner to that of Example 1-2) to give the object compound (48mg).

mp: 211-213° C.

Rf: 0.54 (CHCl₃ :MeOH:AcOH=16:1:1).

The object compounds in Examples 159 to 166 could be obtained byhydrolyzing the corresponding ethyl ester compound (I-c) with an aqueousNaOH in a similar manner to that of Example 9.

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 159

mp: >250° C.

Rf: 0.12 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 160

mp: >250° C.

Rf: 0.10 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 161

mp: >250° C.

Rf: 0.12 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 162

mp: >250° C.

Rf: 0.13 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 163

mp: 245° C. (dec.).

Rf: 0.13 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 164

mp: >250° C.

Rf: 0.13 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 165

Rf: 0.37 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 166

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:1:1).

The object compounds in Examples 167 to 169 could be obtained byhydrolyzing the corresponding benzyl ester compound (I-c) with anaqueous NaOH in a similar manner to that of Example 1-2) or 16.

The physico-chemical properties of those object compounds are providedhereinbelow.

EXAMPLE 167

mp: 171-174° C.

Rf: 0.51 (CHCl₃ :McOH:AcOH=16:1:1).

FAB MS m/z: 563 [M+H]⁺.

EXAMPLE 168

mp: 165-175° C.

Rf: 0.51 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB MS m/z: 549 [M+H]⁺.

EXAMPLE 169

mp: 132-136° C.

Rf: 0.31 (CHCl₃ :MeOH:28% aq. ammonia=65:25:4).

EXAMPLE 170

N-Phenylacetyl-L-Leu-D-Trp(CH₃)-D-4-thiazolylalanine-·HCl was hydrolyzedwith 1N NaOH in a similar manner to that of Example 1-2) to give theobject compound.

mp: 112-116° C.

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:1:1).

FAB MS m/z: 604 [M+H]⁺.

EXAMPLE 171

N-Cyclohexyloxycarbonyl-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅ (0.25 g) washydrolyzed with 1N NaOH (1 ml) in DMF (3 ml) in a similar manner to thatof Example 9 to give the object compound (0.16 g).

Rf: 0.36 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 172

N-Phenylacetyl-L-Leu-D-Trp(CHO)-D-Phe-OPac (0.20 g) was dissolved in amixture of DMF (2 ml) and acetic acid (2 ml), and Zn powder (0.20 g) wasadded to the mixture at room temperature. After being stirred for 3hours at the same temperature, the mixture was filtered and concentratedin vacuo. The residue was dissolved in ethyl acetate and the solutionwas washed with 0.5N HCl, dried over magnesium sulfate and concentratedin vacuo. The residue was triturated with ethyl ether to give the objectcompound (0.16 g).

mp: 230° C. (dec.)

Rf: 0.51 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 611.

EXAMPLE 173

Boc-D-allolle-L-Leu-D-Trp(CHO)-D-Phe-OPac (0.16 g), zinc powder (0.16 g)and acetic acid (1.6 ml) were reacted in DMF (1.6 ml) in a similarmanner to that of Example 172 to give the object compound (0.11 g).

mp: 197° C. (dec.).

Rf: 0.49 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 707.

EXAMPLE 174

A solution ofN-[1(S)-methoxycarbonyl-2(S)-methylbutylcarbamoyl]-L-Leu-D-Trp(CH₃)-D-Phe-OBzl(270 mg) in DMF (20 ml) and water (1 ml) was hydrogenated over 10% Pd-C(50 mg) at 3 atmospheric pressure of hydrogen for 1 hour at roomtemperature. After the solution was filtered and the filtrate wasconcentrated in vacuo, the residue was crystallized from ethyl acetateand ether to give the object compound (198 mg).

mp: 210-212° C.,

Rf: 0.48 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 175

N-[1(S)-Methoxycarbonyl-2(S)-methylbutylcarbamoyl]-L-Leu-D-Trp(CH₃)-D-Phe-OBzl(70 mg) and 1N NaOH (1 ml) in DMF (2 ml) were reacted in a similarmanner to that of Example 1-2) to give the object compound (50 mg).

mp: 221-225° C.

Rf: 0.42 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 176

To a solution of cyclohexanol (0.10 ml) in tetrahydrofuran (3 ml) wasadded trichloromethyl chloroformate (0.13 ml) at room temperature. Thissolution was refluxed for 11 hours and the solvent was evaporated atatmospheric pressure in vacuo. The residual oil was dissolved in DMF (10ml), and 2HCl·H-Leu-D-Trp(CH₃)-D-Pya-OEt (0.50 g) was added. The mixturewas adjusted to about pH 7 with NMM (Ca. 0.2 g). After 10 minutes, thesolvent was evaporated in vacuo, and the residue was dissolved in ethylacetate (20 ml). This solution was washed with 1N HCl, saturated sodiumbicarbonate and brine successively, dried over magnesium sulfate andthen concentrated in vacuo. The residual solid was triturated with ethylether to give the object compound (0.29 g).

mp: 128-130° C.

Rf: 0.50 (CHCl₃ :MeOH=9:1).

EXAMPLE 177

To a solution of N-phenylacetyl-L-Leu-D-Trp(CH₃)-D-His(Tos)-OBzl (78 mg)in DMF (2 ml) was added pyridine hydrochloride (0.15 g) at roomtemperature. After stirring for 2 hours, the solvent was removed byevaporation in vacuo and the residue was dissolved in ethyl acetate (20ml). This solution was washed with 1M sodium bicarbonate (10 ml), driedover magnesium sulfate and evaporated in vacuo to give the objectcompound (45 mg).

mp: 118-126° C.

Rf: 0.28 (CHCl₃ :MeOH=9:1).

EXAMPLE 178

Boc-D-phenylglycyl-L-Leu D Trp(CH₃)-D-Phe-OH (0.1 g), trifluoroaceticacid (1.5 ml) and anisole (0.2 ml) were reacted in a similar manner tothat of Preparation 1-2) to give the object compound (90 mg).

mp: 135-165° C.

Rf: 0.20 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 612 [M+H]⁺.

EXAMPLE 179

Boc-L-Phenylglycyl-L-Leu-D-Trp(CH₃)-D-Phe-OH (0.11 g), TFA (1.5 ml) andanisole (0.2 ml) were reacted in a similar manner to that of Preparation1-2) to give the object compound (107 mg).

mp: 145-170° C.

Rf: 0.20 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 612 [M+H]⁺.

EXAMPLE 180

The object compound could be obtained by reacting the correspondingstarting compounds (II) and (III) in a similar manner to that of Example1-1).

mp: 197-202° C.

Rf: 0.52 (CHCl₃ :MeOH=9:1).

The object compounds in Examples 181 to 215 were obtained by reactingthe corresponding starting compounds (II) and (III) in a similar mannerto that of Example 1-1), preferably in the presence of a suitable base.

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 181

Rf: 0.52 (CHCl₃ :MeOH=9:1).

EXAMPLE 182

Rf: 0.61 (CHCl₃ :MeOH=9:1).

EXAMPLE 183

Rf: 0.80 (CHCl₃ :MeOH=9:1).

EXAMPLE 184

mp: 192-193° C.

Rf: 0.67 (CHCl₃ :MeOH=9:1).

EXAMPLE 185

mp: 155-160° C.

Rf: 0.82 (CHCl₃ :MeOH=9:1).

EXAMPLE 186

Rf: 0.72 (CHCl₃ :MeOH=9:1).

EXAMPLE 187

Rf: 0.34 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 188

mp: 180-185° C.

Rf: 0.50 (CHCl₃ :MeOH=9:1).

EXAMPLE 189

mp: 125-127° C.

Rf: 0.46 (CHCl₃ :MeOH=9:1).

EXAMPLE 190

Rf: 0.78 (CHCl₃ :MeOH=9:1).

EXAMPLE 191

Rf: 0.58 (CHCl₃ MeOH=9:1).

EXAMPLE 192

mp: 143-146° C.

Rf: 0.46 (CHCl₃ :MeOH=9:1).

EXAMPLE 193

Rf: 0.40 (CHCl₃ :MeOH=9:1).

EXAMPLE 194

mp: 180° C.

Rf: 0.44 (CHCl₃ :MeOH=9:1).

EXAMPLE 195

mp: 138-140° C.

Rf: 0.42 (CHCl₃ :MeOH=9:1).

EXAMPLE 196

Rf: 0.37 (CHCl₃ :MeOH=9:1).

EXAMPLE 197

Rf: 0.54 (CHCl₃ :MeOH=9:1).

EXAMPLE 198

Rf: 0.66 (CHCl₃ :MeOH=9:1).

EXAMPLE 199

mp: 186-190° C.

Rf: 0.611 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 200

mp : 194-197° C.

Rf: 0.48 (CHCl₃ :MeOH=9:1).

EXAMPLE 201

Rf: 0.39 (CHCl₃ :MeOH=9:1).

EXAMPLE 202

Rf: 0.70 (CHCl₃ :MeOH=9:1).

EXAMPLE 203

mp: 159-161° C.

Rf: 0.53 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 204

mp: 183-185° C.

Rf: 0.58 (CHCl₃ :MeOH=9:1).

EXAMPLE 205

mp: 154-159° C.

Rf: 0.58 (CHCl₁₃ :MeOH=9:1).

EXAMPLE 206

mp: 82-83° C.

Rf: 0.58 (CHCl₃ :MeOH=9:1).

EXAMPLE 207

mp: 164-167° C.

Rf: 0.83 (CHCl₃ :MeOH=9:1).

EXAMPLE 208

mp: 148-153° C.

Rf: 0.58 (CHCl₃ :MeOH=9:1).

EXAMPLE 209

mp: 116-120° C.

Rf: 0.83 (CHCl₃ :MeOH=9:1).

EXAMPLE 210

mp: 88-95° C.

Rf: 0.64 (CHCl₃ :MeOH=9:1).

EXAMPLE 211

mp: 143-149° C.

Rf: 0.57 (CHCl₃ :MeOH=9:1).

EXAMPLE 212

mp: 182-186° C.

Rf: 0.58 (CHCl₃ :MeOH=9:1).

EXAMPLE 213

mp: 155-160° C.

Rf: 0.58 (CHCl₃ :MeOH=9:1).

EXAMPLE 214

mp: 180-181° C.

Rf: 0.58 (CHCl₃ :MeOH=9:1).

EXAMPLE 215

mp: 199-200° C.

Rf: 0.38 (CHCl₃ :MeOH=9:1).

EXAMPLE 216

To a mixture of phenylacetyl chloride (0.27 g) andHCl·H-L-Leu-D-Trp(CHO)-βAla-OPac (0.94 g) in DMF (10 ml) was addedtriethylamine (0.54 ml) at 0° C. After 30 minutes, the solvent wasevaporated in vacuo and the residue was dissolved in ethyl acetate (50ml). The solution was washed with 0.5N hydrochloric acid (30 ml), driedover magnesium sulfate and concentrated in vacuo. The residual solid wastriturated with ethyl ether to give the object compound (0.93 g).

mp: 163-171° C.

Rf: 0.45 (chloroform:methanol=9:1).

The object compounds in Examples 217 to 244 could be obtained byreacting the corresponding starting compounds (I-a) and (IV) in asimilar manner to that of Example 73 or 216.

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 217

mp: 152-153° C.

Rf: 0.48 (CHCl₃ :MeOH=9:1).

EXAMPLE 218

mp: 180-181.5° C.

Rf: 0.57 (CHCl₃ MeOH=9:1).

EXAMPLE 219

mp: 197-199° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 220

mp: 76-79° C.

Rf: 0.54 (CHCl₃ MeOH=9:1).

EXAMPLE 221

mp: 154-160° C.

Rf: 0.64 (CHCl₃ :MeOH=9:1).

EXAMPLE 222

mp: 98-103° C.

Rf: 0.52 (CHCl₃ :MeOH=9:1).

EXAMPLE 223

mp: 171-174° C.

Rf: 0.40 (CHCl₃ :MeOH=9:1).

EXAMPLE 224

mp: 150-153° C.

Rf: 0.52 (CHCl₃ :MeOH=9:1).

EXAMPLE 225

mp: 170-172° C.

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 226

mp: 159-168° C.

Rf: 0.38 (CHCl₃ :MeOH=9:1).

EXAMPLE 227

mp: 77-88° C.

Rf: 0.52 (CHCl₃ :MeOH=9:1).

EXAMPLE 228

mp: 158-162° C.

Rf: 0.55 (CHCl₃ :MeOH=9:1).

EXAMPLE 229

mp: 191-193° C.

Rf: 0.43 (CHCl₃ :MeOH=9:1).

EXAMPLE 230

mp: 158-162° C.

Rf: 0.43 (CHCl₃ :MeOH=9:1).

EXAMPLE 231

mp: 123-126° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 232

mp: 145-146° C.

Rf: 0.60 (CHCl₃ :MeOH=9:1).

EXAMPLE 233

mp: 168-170° C.

Rf: 0.72 (CHCl₃ :MeOH=9:1).

EXAMPLE 234

mp: 180-183° C.

Rf: 0.59 (CHCl₃ :MeOH=9:1).

EXAMPLE 235

mp: 196-204° C.

Rf: 0.49 (CHCl₃ :MeOH=9:1).

EXAMPLE 236

mp: 221-226° C.

Rf: 0.49 (CHCl₃ :MeOH=9:1).

EXAMPLE 237

Rf: 0.47 (CHCl₃ :MeOH=9:1).

EXAMPLE 238

mp: 198-199° C.

Rf: 0.65 (CHCl₃ :MeOH=9:1).

EXAMPLE 239

mp: 104-107° C.

Rf: 0.59 (CHCl₃ :MeOH=9:1).

EXAMPLE 240

mp: 228-230° C.

Rf: 0.57 (CHCl₃ :MeOH=9:1).

EXAMPLE 241

mp: 196-199° C.

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 242

mp: 207-212° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 243

mp: 186-190° C.

Rf: 0.49 (CHCl₃ :MeOH=9:1).

EXAMPLE 244

Rf: 0.49 (CHCl₃ :MeOH=9:1).

The object compounds in Examples 245 to 263 could be obtained byreacting the corresponding starting compounds and (VI) in a similarmanner to that of Example 92.

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 245

mp: 145-148° C.

Rf: 0.68 (CHCl₃ :MeOH=9:1).

EXAMPLE 246

mp: 156-160° C.

Rf: 0.56 (CHCl₃ :MeOH=9:1).

EXAMPLE 247

mp: 143-147° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 248

mp: 106-110° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 249

mp: 116-119° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 250

mp: 140-143° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 251

mp: 156-160° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 252

mp: 128-130° C.

Rf: 0.76 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 253

mp: 120-130° C.

Rf: 0.85 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 254

mp: 145-148° C.

Rf: 0.88 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 255

mp: 165-167° C.

Rf: 0.91 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 256

Rf: 0.37 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 257

Rf: 0.56 (CHCl₃ :MeOH=19:1).

EXAMPLE 258

Rf: 0.45 (CHCl₃ :MeOH=19:1).

EXAMPLE 259

mp: 69-70° C.

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 260

Rf: 0.45 (CHCl₃ :MeOH=19:1).

EXAMPLE 261

Rf: 0.71 (CHCl₃ :MeOH=9:1).

EXAMPLE 262

mp: 120-130° C.

Rf: 0.85 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 263

mp: 120-122° C.

Rf: 0.72 (CHCl₃ :MeOH=9:1).

EXAMPLE 264

To a solution of N-phenylacetyl-L-Leu-D-Trp(Me)-D-Lys(Z)-OBzl (0.10 g)in DMF (2 ml) were added 10%-palladium on activated carbon (30 mg) andammonium formate (0.2 g) at room temperature. After 3 hours, thesuspended mixture was filtered and the filtrate was evaporated in vacuo.The residue was dissolved in 1N hydrochloric acid (1 ml) and purifiedwith "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries)column chromatography (eluent:MeOH), and lyophilized to give the objectcompound (57.4 mg).

mp: 142-160° C.

Rf: 0.26 (chloroform:methanol:28% aqueous ammonia=5:3:).

FAB-MS m/z: 578 [M+H].

EXAMPLE 265

N-Phenylacetyl-L-Leu-D-Trp(CHO)-βAla-OH (0.38 g) and 1N NaOH (5 ml) werereacted in DMF (10 ml) in a similar manner to that of Example 1-2) togive the object compound (0.23 g).

mp: 85-95° C.

Rf: 0.48 (chloroform:methanol:acetic acid=16:1:1).

FAB-MS m/z=507 [M+H].

EXAMPLE 266

N-Phenylacetyl-L-His(Tos)-D-Trp(CHO)-βAla-OMe (0.32 g) and pyridinehydrochloride (0.6 g) were reacted in DMF (6 ml) in a similar manner tothat of Example 177 to give the object compound (0.20 g).

mp: 160-166° C.

Rf: 0.30 (10% MeOH in CHCl₃).

EXAMPLE 267

Boc-D-alloIle-L-Leu-D-Trp-D-Pya-OEt (2.0 g), and 4N HCl in dioxane (35ml) were reacted in a similar manner to that of Preparation 1-2) to givethe object compound (1.82 g).

Rf: 0.62 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 268

Boc-D-alloIle-L-Leu-D-Trp(CHO)-D-Glu(OBzl)-OH (0.67 g), TFA (10 ml) andanisole (1 ml) were reacted in a similar manner to that of Preparation1-2) to give the object compound (0.60 g).

mp: 85-110° C.

Rf: 0.16 (chloroform:methanol:acetic acid=16:1:1).

FAB-MS m/z: 679 [M+H].

The object compounds in Examples 269 to 292, and 349 were obtained byreacting the corresponding Pac ester compounds (I-c), Zn powder, aceticacid and DMF in a similar manner to that of Example 172.

The object compounds in Examples 293 to 294, 297 to 330, 333 to 345,347-348, and 350 to 355 were obtained by reacting the correspondingmethyl, ethyl, benzyl or Pac ester compound (I-c) with an aqueous NaOHin a similar manner to that of Example 1-2), 9 or 16.

The object compounds in Examples 295 to 296 and 331 to 332 were obtainedby hydrogenating the corresponding benzyl, ester compound (I-c) in asimilar manner to that of Preparation 1-4).

EXAMPLE 346

N-(ε-Caprolactam-3-ylaminocarbonyl)-L-Leu-OH (293 mg),2HCl·H-D-Trp(Me)-D-Pya-OEt (400 mg), WSCD (159 mg), HOBt (139 mg), Et₃ N(87 mg) and DMF (10 ml) were reacted in a similar manner to that ofExample 1-1) to give the object compound (411 mg).

The physico-chemical properties of these object compounds of Examples269 to 355 are provided hereinbelow.

EXAMPLE 269

mp: 165-168° C.

Rf: 0.52 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 669 [M+H].

EXAMPLE 270

mp: 152-157° C.

Rf: 0.41 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 683 [M+H].

EXAMPLE 271

mp: 150-153° C.

Rf: 0.52 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 719 [M+H].

EXAMPLE 272

mp: 196-199° C.

Rf: 0.52 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 719 [M+H].

EXAMPLE 273

mp: 90-100° C.

Rf: 0.50 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 649 [M+H].

EXAMPLE 274

mp: 140-148° C.

Rf: 0.50 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 708 [M+H].

EXAMPLE 275

mp: 95-105° C.

Rf: 0.44 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 670 [M+H].

EXAMPLE 276

mp: 183-185° C.

Rf: 0.36 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 671 [M+H].

EXAMPLE 277

mp: 145-150° C.

Rf: 0.46 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 664 [M+H].

EXAMPLE 278

mp: 205-207° C.

Rf: 0.49 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 675 [M+H].

EXAMPLE 279

mp: 90-130° C.

Rf: 0.41 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 280

mp: 89-120° C.

Rf: 0.40 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z 678 [M+H].

EXAMPLE 281

mp: 145-150° C.

Rf: 0.51 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 663 [M+H].

EXAMPLE 282

mp: 165-170° C.

Rf: 0.49 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 733 [M+H].

EXAMPLE 283

mp: 156-160° C.

Rf: 0.47 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 733 [M+H].

EXAMPLE 284

mp: 165-200° C.

Rf: 0.29 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 616 [M+H].

EXAMPLE 285

mp: 137-142° C.

Rf: 0.46 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 644 [M+H].

EXAMPLE 286

mp: 155-157° C.

Rf: 0.48 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 658 [M+H].

EXAMPLE 287

mp: 111-128° C.

Rf: 0.48 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 673 [M+H].

EXAMPLE 288

mp: 80-108° C.

Rf: 0.47 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 817 [M+K].

EXAMPLE 289

mp: 110-113° C.

Rf: 0.49 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 290

mp: 195° C. (dec.).

Rf: 0.52 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 535 [M+H].

EXAMPLE 291

mp: 165-169° C.

Rf: 0.45 (CHCl₃ :MeOH:AcOH=16:1:1).

FAB-MS m/z: 630 [M+H].

EXAMPLE 292

Rf: 0.32 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 293

Rf: 0.32 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 294

Rf: 0.68 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 295

mp: 188-190° C.

Rf: 0.31 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 296

mp: 202-205° C.

Rf: 0.29 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 297

Rf: 0.10 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 298

Rf: 0.07 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 299

Rf: 0.10 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 300

Rf: 0.09 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 301

Rf: 0.11 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 302

Rf: 0.25 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 303

Rf: 0.22 (CHCl₁₃ :MeOH:AcOH=16:1:1).

EXAMPLE 304

Rf: 0.29 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 305

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 306

Rf: 0.45 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 307

Rf: 0.29 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 308

Rf: 0.33 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 309

Rf: 0.53 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 310

Rf: 0.28 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 311

Rf: 0.25 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 312

Rf: 0.62 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 313

Rf: 0.64 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 314

Rf: 0.46 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 315

mp: 248° C. (dec.).

Rf: 0.27 (CHCl₃ :MeOH:AcOH=8:1:1).

Rf: 0.32 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 317

mp: 142-147° C.

Rf: 0.34 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 318

Rf: 0.31 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 319

Rf: 0.37 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 320

Rf: 0.37 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 321

Rf: 0.20 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 322

Rf: 0.32 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 323

Rf: 0.36 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 324

Rf: 0.36 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 325

Rf: 0.36 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 326

Rf: 0.54 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 327

Rf: 0.54 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 328

Rf: 0.53 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 329

Rf: 0.53 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 330

Rf: 0.53 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 331

mp: 205-208° C.

Rf: 0.27 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 332

mp: 200-210° C.

Rf: 0.34 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 333

mp: 146-150° C.

Rf: 0.74 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 334

mp: 138-141° C.

Rf: 0.70 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 335

mp: 80-90° C.

Rf: 0.42 (CHCl₃ :MeOH:AcOH=16:1:1).

Rf: 0.72 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 336

Rf: 0.61 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 337

mp: 103-110° C.

Rf: 0.46 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 338

mp: 128-137° C.

Rf: 0.47 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 339

mp: 105-115° C.

Rf: 0.48 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 340

mp: 133-136° C.

Rf: 0.47 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 341

mp: 158-162° C.

Rf: 0.42 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 342

Rf: 0.64 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 343

Rf: 0.56 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 344

Rf: 0.30 (CHCl₃ :MeOH=9:1).

EXAMPLE 345

Rf: 0.41 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 346

mp: 210-212° C.

Rf: 0.44 (CHCl₃ :MeOH=9:1).

EXAMPLE 347

Rf: 0.50 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 348

mp: 129-135° C.

Rf: 0.37 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 349

mp: 91-113° C.

Rf: 0.53 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 350

mp: 162-167° C.

Rf: 0.12 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 351

mp : 133-140° C.

Rf: 0.52 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 352

mp: 208-210° C.

Rf: 0.72 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 353

mp: 113-123° C.

Rf: 0.72 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 354

mp: 160-164° C .

Rf: 0.80 (CHCl₃ :MeOH:AcOH=8:1:1).

EXAMPLE 355

Rf: 0.30 (CHCl₃ :MeOH:AcOH=8:1:1).

The object compounds in Examples 356 to 374, 376 to 377, 380 to 382, 384to 392 and 400 could be obtained by reacting the correspondingcarboxylic acid compounds (I-i) with substituted amines in a similarmanner to that of Example 1-1).

The object compounds in Examples 375, 378 to 379, and 393 to 399 couldbe obtained by reacting the corresponding carboxylic acid or its ethylester compounds (I-i) with optionally substituted amines in a similarmanner to that of Example 383.

EXAMPLE 383

N-(Hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-D-Trp(Me)-D-Pya-OEt (0.20 g)was dissolved in 2.4N ammonia in methanol (10 ml) and the mixture wasallowed to stand for 3 days at room temperature. Then the mixture wasconcentrated in vacuo and the residue was triturated with diethyl ether(10 ml) to give the object compound (0.18 g).

EXAMPLE 401

N-(Hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-D-Trp(Me)-D-Pya-2-[(5S)-5-ethoxycarbonyl-2-oxopyrrolidin-1-yl]-ethylamide(70 mg) and 2.4N NH₃ in MeOH (5 ml) were reacted in a similar manner tothat of Example 383 to give the object compound (42.7 mg).

The physico-chemical properties of the object compounds of Examples 356to 401 are provided hereinbelow.

EXAMPLE 356

mp: 220-224° C.

RF: 0.47 (CHCl₃ :MeOH=9:1).

EXAMPLE 357

mp: 196-203° C.

Rf: 0.36 (CHCl₃ :MeOH=9:1).

EXAMPLE 358

Rf: 0.62 (CHCl₃ :MeOH=9:1).

EXAMPLE 359

mp: 140-145° C.

Rf: 0.52 (CHCl₃ :MeOH=9:1).

EXAMPLE 360

Rf: 0.56 (CHCl₃ :MeOH=9:1).

EXAMPLE 361

Rf: 0.60 (CHCl₃ :MeOH=9:1).

EXAMPLE 362

Rf: 0.60 (CHCl₃ :MeOH=9:1).

EXAMPLE 363

Rf: 0.58 (CHCl₃ :MeOH=9:1).

EXAMPLE 364

Rf: 0.58 (CHCl₃ :MeOH=9:1).

EXAMPLE 365

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 366

Rf: 0.53 (CHCl₃ :MeOH=9:1).

EXAMPLE 367

Rf: 0.52 (CHCl₃ :MeOH=9:1).

EXAMPLE 368

Rf: 0.83 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 369

Rf: 0.83 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 370

Rf: 0.83 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 371

Rf: 0.83 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 372

Rf: 0.83 (CHCl₃ :MeOH:AcOH=8:2:1).

EXAMPLE 373

mp: 190-195° C.

Rf: 0.72 (CHCl₃ :MeOH=9:1).

EXAMPLE 374

mp: 195-197° C.

Rf: 0.76 (CHCl₃ :MeOH=9:1).

EXAMPLE 375

Rf: 0.41 (CHCl₃ :MeOH=9:1).

EXAMPLE 376

Rf: 0.44 (CHCl₃ :MeOH=9:1).

EXAMPLE 377

mp: 160-164° C.

Rf: 0.49 (CHCl₃ :MeOH=9:1).

EXAMPLE 378

Rf: 0.44 (CHCl₃ :MeOH=9:1).

EXAMPLE 379

mp: 200-203° C.

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 380

mp: 76-78° C.

Rf: 0.54 (CHCl₃ :MeOH=9:1).

EXAMPLE 381

mp: 75-78° C.

Rf: 0.49 (CHCl₃ :MeOH=9:1).

EXAMPLE 382

Rf: 0.64 (CHCl₃ :MeOH=9:1).

EXAMPLE 383

mp: 110-112° C.

Rf: 0.50 (CHCl₃ :MeOH=9:1).

EXAMPLE 384

mp: 140-145° C.

Rf: 0.64 (CHCl₃ :MeOH=9:1).

EXAMPLE 385

Rf: 0.65 (CHCl₃ :MeOH=9:1).

EXAMPLE 386

Rf: 0.62 (CHCl₃ :MeOH=9:1).

EXAMPLE 387

Rf: 0.62 (CHCl₃ :MeOH=9:1).

EXAMPLE 388

Rf: 0.62 (CHCl₃ :MeOH=9:1).

EXAMPLE 389

Rf: 0.65 (CHCl₃ :MeOH=9:1).

EXAMPLE 390

Rf: 0.45 (CHCl₃ :MeOH=9:1).

EXAMPLE 391

mp: 165-167° C.

Rf: 0.48 (CHCl₃ :MeOH=9:1).

EXAMPLE 392

mp: 142-143° C .

Rf: 0.50 (CHCl₃ :MeOH=9:1).

EXAMPLE 393

mp: 168° C.

Rf: 0.46 (CHCl₃ :MeOH=9:1).

EXAMPLE 394

mp: 120-125° C.

Rf: 0.47 (CHCl₃ :MeOH=9:1).

EXAMPLE 395

mp: 115-125° C .

Rf: 0.47 (CHCl₃ :MeOH=9:1).

EXAMPLE 396

mp: 168° C.

Rf: 0.41 (CHCl₃ :MeOH=9:1).

EXAMPLE 397

mp: 215° C.

Rf: 0.35 (CHCl₃ :MeOH=9:1).

EXAMPLE 398

mp: 108-109° C.

Rf: 0.34 (CHCl₃ :MeOH=19:1).

EXAMPLE 399

mp: 119-120° C.

Rf: 0.28 (CHCl₃ :MeOH=19:1).

EXAMPLE 400

Rf: 0.49 (CHCl₃ :MeOH=9:1).

EXAMPLE 401

mp: 195-197° C.

Rf: 0.26 (CHCl₃ :MeOH=9:1).

EXAMPLE 402

N-(Hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-D-Trp(Me)-OH (400 mg),N-(ethoxycarbonylmethyl)-N-(pyridin-2-ylmethyl)amine (187 mg), HOBT (131mg), WSLD-HCl (150 mg) and DMF (5 ml) were reacted in a similar mannerto that of Example 1-1) to give the object compound (554 mg).

Rf: 0.37 (CHCl₃ :MeOH=20:1).

EXAMPLE 403

N-(Hexahydro-1H-azepin-1-ylcarbonyl)-L-Leu-D-Trp(Me)-OH (400 mg),N-(ethoxycarbonylmethyl)-N-[2-(pyridin-2-yl)ethyl]amine dihydrochloride(271 mg), HOBT (131 mg), WSCD (150 mg), N-methylmorpholine (98 mg) andDMF (5 ml) were reacted in substantially the same manner to that ofExample 92 to give the object compound (288 mg).

Rf: 0.32 (CHCl₃ :MeOH=20:1).

EXAMPLE 404

Cyclohexyl isocyanate (60 mg),2HCl·H-D-alloIle-L-Leu-D-Trp(Me)-D-Pya-OEt (300 mg), Et₃ N (87 mg) andDMF (10 ml) were reacted in a similar manner to that of Example 4-1) togive the object compound (260 mg).

mp: 235-237° C.

Rf: 0.45 (CHCl₃ :MeOH=9:1).

EXAMPLE 405

The object compound was obtained in 90.8% yield in substantially thesame manner as that of Example 406.

mp: 111-115° C.

Rf: 0.46 (CHCl₃ :MeOH=9:1).

EXAMPLE 406

Boc-L-Leu-D-Trp(CH₃)-D-Pya-OC₂ H₅ (1.70 g) in TFA (20 ml) and anisole (2ml) was reacted at 0° C. for 1 hour and then the product was reactedwith 4N HCl in 1,4-dioxane in a similar manner to that of Preparation1-2) to give the object compound (1.60 g).

mp: 141-145° C.

Rf: (CHCl₃ :MeOH=9:1).

The object compounds in Examples 407 to 416 could be obtained byremoving t-butoxycarbonyl groups from the corresponding startingcompounds (I-b) with TFA and anisole in a similar manner to that ofPreparation 1-2).

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 407

mp: 146-156° C.

Rf: 0.35 (CHCl₃ :MeOH=9:1).

EXAMPLE 408

Rf: 0.26 (CHCl₃ :MeOH=9:1).

EXAMPLE 409

Rf: 0.26 (CHCl₃ MeOH=9:1).

EXAMPLE 410

mp: 86-103° C.

Rf: 0.36 (CHCl₃ :MeOH=9:1).

EXAMPLE 411

mp: 76-102° C.

Rf: 0.20 (CHCl₃ :MeOH:AcOH=16:1:1).

EXAMPLE 412

mp: 152-165° C.

Rf: 0.32 (CHCl₃ :MeOH=9:1).

EXAMPLE 413

Rf: 0.27 (CHCl₃ :MeOH=9:1).

EXAMPLE 414

Rf: 0.26 (CHCl₃ :MeOH=9:1).

EXAMPLE 415

mp: 194-202° C.

Rf: 0.26 (CHCl₃ :MeOH=9:1).

EXAMPLE 416

Rf: 0.26 (CHCl₃ :MeOH=9:1).

The object compounds in Examples 417 to 426 could be obtained byreacting the corresponding starting compounds with 4N hydrogen chloridein ethyl acetate in a similar manner to that of Example 22.

The physico-chemical properties of these object compounds are providedhereinbelow.

EXAMPLE 417

mp: 141-146° C.

Rf: 0.87 (CHCl₃ :MeOH:AcOH=8:1:1).

FAB-MS m/z: =678 [M+H].

EXAMPLE 418

mp: 103-120° C.

EXAMPLE 419

Rf: 0.41 (CHCl₃ :MeOH=9:1).

EXAMPLE 420

Rf: 0.44 (CHCl₃ :MeOH=9:1).

EXAMPLE 421

Rf: 0.49 (CHCl₃ :MeOH=9:1).

EXAMPLE 422

Rf: 0.44 (CHCl₃ :MeOH=9:1).

EXAMPLE 423

Rf: 0.51 (CHCl₃ :MeOH=9:1).

EXAMPLE 424

Rf: 0.65 (CHCl₃ :MeOH=9:1).

EXAMPLE 425

mp: 110-135° C.

Rf: 0.50 (CHCl₃ :MeOH=9:1).

EXAMPLE 426

mp: 105-145° C.

Rf: 0.49 (CHCl₃ :MeOH=9:1).

The compounds of Examples 427 to 429 could be obtained by reacting thecorresponding starting compounds and (III) in a similar manner to thatof Example (1-1).

The physicochemical properties of these object compounds are providedhereinbelow.

EXAMPLE 427

Rf: 0.44 (CHCl₃ :MeOH=9:1).

EXAMPLE 428

Rf: 0.44 (CHCl₃ :MeOH=9:1).

EXAMPLE 429

mp: 110-112° C.

Rf : 0.50 (CHCl₃ :MeOH=9:1).

The compounds of Examples 430 to 432 could be obtained by reacting thecorresponding starting compounds (V) and (VI) in a similar manner tothat of Example 92.

The physicochemical properties of these object compounds are providedhereinbelow.

EXAMPLE 430

Rf: 0.44 (CHCl₃ :MeOH=9:1).

EXAMPLE 431

Rf: 0.44 (CHCl₃ :MeOH=9:1).

EXAMPLE 432

mp: 110-112° C.

Rf: 0.50 (CHCl₃ :MeOH=9:1).

The object compounds obtained in the above Examples are given in thefollowing Table.

    __________________________________________________________________________    Example Nos.                                                                         Chemical Formulae                                                      __________________________________________________________________________     1-1)                                                                                 ##STR9##                                                                 2)                                                                                 ##STR10##                                                              2-1)                                                                                 ##STR11##                                                                2)                                                                                 ##STR12##                                                              3-1)                                                                                 ##STR13##                                                                2)                                                                                 ##STR14##                                                               4-1)                                                                                ##STR15##                                                              4-2)                                                                                 ##STR16##                                                              5-1)                                                                                 ##STR17##                                                                2)                                                                                 ##STR18##                                                              6-1)                                                                                 ##STR19##                                                                     ##STR20##                                                              7-1)                                                                                 ##STR21##                                                                2)                                                                                 ##STR22##                                                              8-1)                                                                                 ##STR23##                                                                2)                                                                                 ##STR24##                                                              9                                                                                    ##STR25##                                                              10                                                                                   ##STR26##                                                              11                                                                                   ##STR27##                                                              12                                                                                   ##STR28##                                                              13                                                                                   ##STR29##                                                              14                                                                                   ##STR30##                                                              15                                                                                   ##STR31##                                                              16                                                                                   ##STR32##                                                              17                                                                                   ##STR33##                                                              18                                                                                   ##STR34##                                                              19                                                                                   ##STR35##                                                              20                                                                                   ##STR36##                                                              21                                                                                   ##STR37##                                                              22                                                                                   ##STR38##                                                              23                                                                                   ##STR39##                                                              24                                                                                   ##STR40##                                                              25                                                                                   ##STR41##                                                              26                                                                                   ##STR42##                                                              27                                                                                   ##STR43##                                                              28                                                                                   ##STR44##                                                              29                                                                                   ##STR45##                                                              30    (n-C.sub.4 H.sub. 9).sub.2 NCOLLeuDTrp(CH.sub.3)DPyaOC.sub.2                  H.sub.5                                                                 31    (n-C.sub.3 H.sub.7).sub.2 NCOLLeuDTrp(CH.sub.3)DPyaOC.sub.2                   H.sub.5                                                                 32    n-C.sub.7 H.sub.15NHCOLLeuDTrp(CH.sub.3)DPyaOC.sub.2 H.sub.5            33    (i-C.sub.4 H.sub.9).sub.2 NCOLLeuDTrp(CH.sub.3)DPyaOC.sub.2                   H.sub.5                                                                 34                                                                                   ##STR46##                                                              35                                                                                   ##STR47##                                                              36                                                                                   ##STR48##                                                              37                                                                                   ##STR49##                                                              38                                                                                   ##STR50##                                                              39                                                                                   ##STR51##                                                              40                                                                                   ##STR52##                                                              41                                                                                   ##STR53##                                                              42                                                                                   ##STR54##                                                              43                                                                                   ##STR55##                                                              44                                                                                   ##STR56##                                                              45                                                                                   ##STR57##                                                              46    (C.sub.2 H.sub.5).sub.2 NCOLLeuDTrp(CH.sub.3)DPyaOC.sub.2 H.sub.5       47    (i-C.sub.3 H.sub.7).sub.2 NCOLLeuDTrp(CH.sub.3)DPyaOC.sub.2                   H.sub.5                                                                 48                                                                                   ##STR58##                                                              49                                                                                   ##STR59##                                                              50                                                                                   ##STR60##                                                              51                                                                                   ##STR61##                                                              52                                                                                   ##STR62##                                                              53                                                                                   ##STR63##                                                              54                                                                                   ##STR64##                                                              55                                                                                   ##STR65##                                                              56                                                                                   ##STR66##                                                              57                                                                                   ##STR67##                                                              58                                                                                   ##STR68##                                                              59                                                                                   ##STR69##                                                              60                                                                                   ##STR70##                                                              61                                                                                   ##STR71##                                                              62                                                                                   ##STR72##                                                              63                                                                                   ##STR73##                                                              64                                                                                   ##STR74##                                                              65                                                                                   ##STR75##                                                              66                                                                                   ##STR76##                                                              67                                                                                   ##STR77##                                                              68                                                                                   ##STR78##                                                              69                                                                                   ##STR79##                                                              70                                                                                   ##STR80##                                                              71                                                                                   ##STR81##                                                              72                                                                                   ##STR82##                                                              73                                                                                   ##STR83##                                                              74                                                                                   ##STR84##                                                              75                                                                                   ##STR85##                                                              76                                                                                   ##STR86##                                                              77                                                                                   ##STR87##                                                              78                                                                                   ##STR88##                                                              79                                                                                   ##STR89##                                                              80                                                                                   ##STR90##                                                              81                                                                                   ##STR91##                                                              82                                                                                   ##STR92##                                                              83                                                                                   ##STR93##                                                              84                                                                                   ##STR94##                                                              85                                                                                   ##STR95##                                                              86                                                                                   ##STR96##                                                              87                                                                                   ##STR97##                                                              88                                                                                   ##STR98##                                                              89                                                                                   ##STR99##                                                              90                                                                                   ##STR100##                                                             91                                                                                   ##STR101##                                                             92                                                                                   ##STR102##                                                             93                                                                                   ##STR103##                                                             94                                                                                   ##STR104##                                                             95                                                                                   ##STR105##                                                             96                                                                                   ##STR106##                                                             97                                                                                   ##STR107##                                                             98    BocDalloIleLLeuDTrp(CHO)DPheOPac                                        99                                                                                   ##STR108##                                                            100                                                                                   ##STR109##                                                            101                                                                                   ##STR110##                                                            102                                                                                   ##STR111##                                                            103                                                                                   ##STR112##                                                            104                                                                                   ##STR113##                                                            105    (n-C.sub.4 H.sub.9).sub.2 NCOLLeuDTrp(CH.sub.3)DPyaONa                 106    (n-C.sub.3 H.sub.7).sub.2 NCOLLeuDTrp(CH.sub.3)DPyaONa                 107    n-C.sub.7 H.sub.15NHCOLLeuDTrp(CH.sub.3)DPyaONa                        108    (i-C.sub.4 H.sub.9).sub.2 NCOLLeuDTrp(CH.sub.3)DPyaONa                 109                                                                                   ##STR114##                                                            110                                                                                   ##STR115##                                                            111                                                                                   ##STR116##                                                            112                                                                                   ##STR117##                                                            113                                                                                   ##STR118##                                                            114                                                                                   ##STR119##                                                            115                                                                                   ##STR120##                                                            116                                                                                   ##STR121##                                                            117                                                                                   ##STR122##                                                            118                                                                                   ##STR123##                                                            119                                                                                   ##STR124##                                                            120                                                                                   ##STR125##                                                            121    (C.sub.2 H.sub.5).sub.2 NCOLLeuDTrp(CH.sub.3)DPyaONa                   122    (i-C.sub.3 H.sub.7).sub.2 NCOLLeuDTrp(CH.sub.3)DPyaONa                 123                                                                                   ##STR126##                                                            124                                                                                   ##STR127##                                                            125                                                                                   ##STR128##                                                            126                                                                                   ##STR129##                                                            127                                                                                   ##STR130##                                                            128                                                                                   ##STR131##                                                            129                                                                                   ##STR132##                                                            130                                                                                   ##STR133##                                                            131                                                                                   ##STR134##                                                            132                                                                                   ##STR135##                                                            133                                                                                   ##STR136##                                                            134                                                                                   ##STR137##                                                            135                                                                                   ##STR138##                                                            136                                                                                   ##STR139##                                                            137                                                                                   ##STR140##                                                            138                                                                                   ##STR141##                                                            139                                                                                   ##STR142##                                                            140                                                                                   ##STR143##                                                            141                                                                                   ##STR144##                                                            142                                                                                   ##STR145##                                                            143                                                                                   ##STR146##                                                            144                                                                                   ##STR147##                                                            145                                                                                   ##STR148##                                                            146                                                                                   ##STR149##                                                            147                                                                                   ##STR150##                                                            148                                                                                   ##STR151##                                                            149                                                                                   ##STR152##                                                            150                                                                                   ##STR153##                                                            151                                                                                   ##STR154##                                                            152                                                                                   ##STR155##                                                            153                                                                                   ##STR156##                                                            154                                                                                   ##STR157##                                                            155                                                                                   ##STR158##                                                            156                                                                                   ##STR159##                                                            157                                                                                   ##STR160##                                                            158                                                                                   ##STR161##                                                            159                                                                                   ##STR162##                                                            160                                                                                   ##STR163##                                                            161                                                                                   ##STR164##                                                            162                                                                                   ##STR165##                                                            163                                                                                   ##STR166##                                                            164                                                                                   ##STR167##                                                            165                                                                                   ##STR168##                                                            166                                                                                   ##STR169##                                                            167                                                                                   ##STR170##                                                            168                                                                                   ##STR171##                                                            169                                                                                   ##STR172##                                                            170                                                                                   ##STR173##                                                            171                                                                                   ##STR174##                                                            172                                                                                   ##STR175##                                                            173    BocD alloIleLLeuDTrp(CHO)DPheOH                                        174                                                                                   ##STR176##                                                            175                                                                                   ##STR177##                                                            176                                                                                   ##STR178##                                                            177                                                                                   ##STR179##                                                            178                                                                                   ##STR180##                                                            179                                                                                   ##STR181##                                                            180                                                                                   ##STR182##                                                            181                                                                                   ##STR183##                                                            182                                                                                   ##STR184##                                                            183                                                                                   ##STR185##                                                            184                                                                                   ##STR186##                                                            185                                                                                   ##STR187##                                                            186                                                                                   ##STR188##                                                            187                                                                                   ##STR189##                                                            188                                                                                   ##STR190##                                                            189                                                                                   ##STR191##                                                            190                                                                                   ##STR192##                                                            191                                                                                   ##STR193##                                                            192                                                                                   ##STR194##                                                            193                                                                                   ##STR195##                                                            194    (Me).sub.2 NCOCH.sub.2 NHCOLLeuDTrp(Me)DPyaOEt                         195    (Me).sub.2 NCO(CH.sub.2).sub.2 NHCOLLeuDTrp(Me)DPyaOEt                 196                                                                                   ##STR196##                                                            197                                                                                   ##STR197##                                                            198                                                                                   ##STR198##                                                            199                                                                                   ##STR199##                                                            200                                                                                   ##STR200##                                                            201                                                                                   ##STR201##                                                            202                                                                                   ##STR202##                                                            203                                                                                   ##STR203##                                                            204    BocLIleDTrp(CHO)βAlaOMe                                           205    BocLNleDTrp(CHO)βAlaOMe                                           206    BocDLeuDTrp(CHO)βAlaOMe                                           207    BocLLeuDTrp(CHO)DGlu(OBzl)OPac                                         208    BocLLeuDTrp(CHO)βAlaOPac                                          209    BocLLeuDTrp(Me)DPheOBzl                                                210    BocLHis(Tos)DTrp(CHO)βAlaOMe                                      211    BocLPyaDTrp(CHO)βAlaOMe                                           212    BocLPheDTrp(CHO)βAlaOMe                                           213    BocLChaDTrp(CHO)βAlaOMe                                           214    BocL-1-NalDTrp(CHO)βAlaOMe                                        215                                                                                   ##STR204##                                                            216                                                                                   ##STR205##                                                            217                                                                                   ##STR206##                                                            218                                                                                   ##STR207##                                                            219                                                                                   ##STR208##                                                            220                                                                                   ##STR209##                                                            221                                                                                   ##STR210##                                                            222                                                                                   ##STR211##                                                            223                                                                                   ##STR212##                                                            224                                                                                   ##STR213##                                                            225                                                                                   ##STR214##                                                            226                                                                                   ##STR215##                                                            227                                                                                   ##STR216##                                                            228                                                                                   ##STR217##                                                            229                                                                                   ##STR218##                                                            230                                                                                   ##STR219##                                                            231    BocDalloIleLLeuDTrp(CHO)DGlu(OBzl)OPac                                 232                                                                                   ##STR220##                                                            233                                                                                   ##STR221##                                                            234                                                                                   ##STR222##                                                            235                                                                                   ##STR223##                                                            236                                                                                   ##STR224##                                                            237                                                                                   ##STR225##                                                            238    BocDalloIleLLeuDTrp(Me)DPyaOEt                                         239                                                                                   ##STR226##                                                            240                                                                                   ##STR227##                                                            241                                                                                   ##STR228##                                                            242                                                                                   ##STR229##                                                            243                                                                                   ##STR230##                                                            244                                                                                   ##STR231##                                                            245                                                                                   ##STR232##                                                            246    BocDalloIleLLeuDTrp(CHO)GlyOPac                                        247    BocDalloIleLLeuDTrp(CHO)NH(CH.sub.2).sub.3 COOPac                      248    BocDalloIleLLeuDTrp(CHO)NH(CH.sub.2).sub.4 COOPac                      249    BocDalloIleLLeuDTrp(CHO)NH(CH.sub.2).sub.5 COOPac                      250    BocDalloIleLLeuDTrp(CHO)LGlu(OBzl)OPac                                 251    BocDalloIleLLeuDTrp(CHO)βAlaOPac                                  252                                                                                   ##STR233##                                                            253                                                                                   ##STR234##                                                            254                                                                                   ##STR235##                                                            255                                                                                   ##STR236##                                                            256                                                                                   ##STR237##                                                            257                                                                                   ##STR238##                                                            258                                                                                   ##STR239##                                                            259                                                                                   ##STR240##                                                            260                                                                                   ##STR241##                                                            261                                                                                   ##STR242##                                                            262                                                                                   ##STR243##                                                            263    BocLLeuDTrp(Me)DPyaOEt                                                 264                                                                                   ##STR244##                                                            265                                                                                   ##STR245##                                                            266                                                                                   ##STR246##                                                            267    2HCl.HDalloIleLLeuDTrp(Me)DPyaOEt                                      268    HCl.HDalloIleLLeuDTrp(CHO)DGlu(OBzl)OH                                 269                                                                                   ##STR247##                                                            270                                                                                   ##STR248##                                                            271                                                                                   ##STR249##                                                            272                                                                                   ##STR250##                                                            273                                                                                   ##STR251##                                                            274                                                                                   ##STR252##                                                            275                                                                                   ##STR253##                                                            276                                                                                   ##STR254##                                                            277                                                                                   ##STR255##                                                            278                                                                                   ##STR256##                                                            279                                                                                   ##STR257##                                                            280                                                                                   ##STR258##                                                            281                                                                                   ##STR259##                                                            282                                                                                   ##STR260##                                                            283                                                                                   ##STR261##                                                            284    BocDalloIleLLeuDTrp(CHO)GlyOH                                          285    BocDalloIleLLeuDTrp(CHO)NH(CH.sub.2 ).sub.3 COOH                       286    BocDalloIleLLeuDTrp(CHO)NH(CH.sub.2).sub.4 COOH                        287    BocDalloIleLLeuDTrp(CHO)NH(CH.sub.2).sub.5 COOH                        288    BocDalloIleLLeuDTrp(CHO)LGlu(OBzl)OH                                   289    BocDalloIleLLeuDTrp(CHO)DGlu(OBzl)OH                                   290                                                                                   ##STR262##                                                            291    BocDalloIleLLeuDTrp(CHO)βAlaOH                                    292                                                                                   ##STR263##                                                            293                                                                                   ##STR264##                                                            294                                                                                   ##STR265##                                                            295                                                                                   ##STR266##                                                            296                                                                                   ##STR267##                                                            297                                                                                   ##STR268##                                                            298                                                                                   ##STR269##                                                            299                                                                                   ##STR270##                                                            300                                                                                   ##STR271##                                                            301                                                                                   ##STR272##                                                            302                                                                                   ##STR273##                                                            303                                                                                   ##STR274##                                                            304                                                                                   ##STR275##                                                            305    (Me).sub.2 NCOCH.sub.2 NHCOLLeuDTrp(Me)DPyaONa                         306    (Me).sub.2 NCO(CH.sub.2).sub.2 NHCOLLeuDTrp(Me)DPyaONa                 307                                                                                   ##STR276##                                                            308                                                                                   ##STR277##                                                            309                                                                                   ##STR278##                                                            310                                                                                   ##STR279##                                                            311                                                                                   ##STR280##                                                            312                                                                                   ##STR281##                                                            313                                                                                   ##STR282##                                                            314                                                                                   ##STR283##                                                            315                                                                                   ##STR284##                                                            316                                                                                   ##STR285##                                                            317                                                                                   ##STR286##                                                            318                                                                                   ##STR287##                                                            319                                                                                   ##STR288##                                                            320                                                                                   ##STR289##                                                            321                                                                                   ##STR290##                                                            322                                                                                   ##STR291##                                                            323                                                                                   ##STR292##                                                            324                                                                                   ##STR293##                                                            325                                                                                   ##STR294##                                                            326                                                                                   ##STR295##                                                            327                                                                                   ##STR296##                                                            328                                                                                   ##STR297##                                                            329                                                                                   ##STR298##                                                            330                                                                                   ##STR299##                                                            331                                                                                   ##STR300##                                                            332                                                                                   ##STR301##                                                            333                                                                                   ##STR302##                                                            334                                                                                   ##STR303##                                                            335                                                                                   ##STR304##                                                            336                                                                                   ##STR305##                                                            337                                                                                   ##STR306##                                                            338                                                                                   ##STR307##                                                            339                                                                                   ##STR308##                                                            340                                                                                   ##STR309##                                                            341                                                                                   ##STR310##                                                            342    BocDalloIleLLeuDTrp(Me)DPyaONa                                         343                                                                                   ##STR311##                                                            344                                                                                   ##STR312##                                                            345                                                                                   ##STR313##                                                            346                                                                                   ##STR314##                                                            347                                                                                   ##STR315##                                                            348                                                                                   ##STR316##                                                            349    BocLLeuDTrp(CHO)DGlu(OBzl)OH                                           350                                                                                   ##STR317##                                                            351                                                                                   ##STR318##                                                            352                                                                                   ##STR319##                                                            353                                                                                   ##STR320##                                                            354                                                                                   ##STR321##                                                            355                                                                                   ##STR322##                                                            356                                                                                   ##STR323##                                                            357                                                                                   ##STR324##                                                            358                                                                                   ##STR325##                                                            359                                                                                   ##STR326##                                                            360                                                                                   ##STR327##                                                            361                                                                                   ##STR328##                                                            362                                                                                   ##STR329##                                                            363                                                                                   ##STR330##                                                            364                                                                                   ##STR331##                                                            365                                                                                   ##STR332##                                                            366                                                                                   ##STR333##                                                            367                                                                                   ##STR334##                                                            368                                                                                   ##STR335##                                                            369                                                                                   ##STR336##                                                            370                                                                                   ##STR337##                                                            371                                                                                   ##STR338##                                                            372                                                                                   ##STR339##                                                            373                                                                                   ##STR340##                                                            374                                                                                   ##STR341##                                                            375                                                                                   ##STR342##                                                            376                                                                                   ##STR343##                                                            377                                                                                   ##STR344##                                                            378                                                                                   ##STR345##                                                            379                                                                                   ##STR346##                                                            380                                                                                   ##STR347##                                                            381                                                                                   ##STR348##                                                            382                                                                                   ##STR349##                                                            383                                                                                   ##STR350##                                                            384                                                                                   ##STR351##                                                            385                                                                                   ##STR352##                                                            386                                                                                   ##STR353##                                                            387                                                                                   ##STR354##                                                            388                                                                                   ##STR355##                                                            389                                                                                   ##STR356##                                                            390                                                                                   ##STR357##                                                            391                                                                                   ##STR358##                                                            392                                                                                   ##STR359##                                                            393                                                                                   ##STR360##                                                            394                                                                                   ##STR361##                                                            395                                                                                   ##STR362##                                                            396                                                                                   ##STR363##                                                            397                                                                                   ##STR364##                                                            398                                                                                   ##STR365##                                                            399                                                                                   ##STR366##                                                            400                                                                                   ##STR367##                                                            401                                                                                   ##STR368##                                                            402                                                                                   ##STR369##                                                            403                                                                                   ##STR370##                                                            404                                                                                   ##STR371##                                                            405    HCl.HLLeuDTrp(Me)DPheOBzl                                              406    2HCl.HLLeuDTrp(Me)DPyaOEt                                              407    HCl.HDLeuDTrp(CHO)βAlaOMe                                         408    HCl.HLNleDTrp(CHO)βAlaOMe                                         409    HCl.HLIleDTrp(CHO)βAlaOMe                                         410    HCl.HLLeuDTrp(CHO)DGlu(OBzl)OPac                                       411    HCl.HLLeuDTrp(CHO)βAlaOPac                                        412    HCl.HL-1-NalDTrp(CHO)βAlaOMe                                      413    HCl.HLCHaDTrp(CHO)βAlaOMe                                         414    HCl.HL PheDTrp(CHO)βAlaOMe                                        415    2HCl.HLPyaDTrp(CHO)βAlaOMe                                        416    TFA.HLHis(Tos)DTrp(CHO)βAlaOMe                                    417                                                                                   ##STR372##                                                            418                                                                                   ##STR373##                                                            419                                                                                   ##STR374##                                                            420                                                                                   ##STR375##                                                            421                                                                                   ##STR376##                                                            422                                                                                   ##STR377##                                                            423                                                                                   ##STR378##                                                            424                                                                                   ##STR379##                                                            425                                                                                   ##STR380##                                                            426                                                                                   ##STR381##                                                            427                                                                                   ##STR382##                                                            428                                                                                   ##STR383##                                                            429                                                                                   ##STR384##                                                            430                                                                                   ##STR385##                                                            431                                                                                   ##STR386##                                                            432                                                                                   ##STR387##                                                            __________________________________________________________________________

In the above table, the configurations accompanied with cis or trans donot mean the absolute configurations, but the relative configurationsonly. The other configurations mean the absolute ones.

What is claimed is:
 1. A peptide compound of the formula (I") ##STR388##or a pharmaceutically acceptable salt thereof in which R¹ is hydrogen oracyl,R² _(c) is lower alkyl, R³ _(c) is an optionally N-substitutedindolylmethyl, R⁴ is hydrogen, lower alkyl, C₆₋₁₀ ar(lower)alkyl,amino(lower)alkyl, protected amino(lower)alkyl, carboxy(lower)alkyl,protected carboxy(lower)alkyl or optionally substituted heterocyclic(lower)alkyl, R⁵ is carboxy, protected carboxy, carboxy(lower)alkyl orprotected carboxy(lower)alkyl, R⁷ is hydrogen or lower alkyl, and A is--O--, --NH--, lower alkylamino or lower alkylene.
 2. The compoundaccording to claim 1, whereinR¹ is acyl, R⁴ is hydrogen, lower alkyl,C₆₋₁₀ ar(lower)alkyl, amino(lower)alkyl, protected amino(lower)alkyl,carboxy(lower)alkyl, protected carboxy(lower)alkyl or optionallysubstituted heterocyclic(lower)alkyl, wherein said heterocyclic group isselected from the group consisting of an unsaturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s), anunsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4nitrogen atoms(s), an unsaturated condensed 7 to 12-memberedheterocyclic group containing 1 to 5 nitrogen atom(s), an unsaturated 3to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s)and 1 to 3 nitrogen atom(s), a saturated 3 to 8-memberedheteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), an unsaturated condensed 7 to 12-membered heterocyclicgroup containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), anunsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2sulfur atom(s) and 1 to 3 nitrogen atom(s), a saturated 3 to 8-memberedheteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), an unsaturated 3 to 8-membered heteromonocyclic groupcontaining a sulfur atom or an unsaturated condensed 7 to 12-memberedheterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogenatom(s); wherein said heterocyclic group may be substituted by one ortwo suitable substituent(s) selected from the group consisting ofhydroxy, protected hydroxy, halogen, lower alkoxy, lower alkyl, amino,nitro, cyano and imino-protective group; and R⁵ is carboxy, esterifiedcarboxy or amidated carboxy.
 3. The compound according to claim 2,whereinR¹ is carbamoyl; saturated or unsaturated, acyclic or cyclicaliphatic acyl optionally substituted by aromatic or heterocyclicgroup(s), aromatic acyl, or heterocyclic acyl, each of which is derivedfrom an organic carboxylic or an organic carbonic or an organic sulfonicor an organic carbamic acid; R⁴ is hydrogen; lower alkyl; C₆ -C₁₀ar(lower)alkyl; amino(lower)alkyl; protected amino(lower)alkyl;carboxy(lower)alkyl; protected carboxy(lower)alkyl; 5- or 6-memberedaromatic heteromonocyclic(lower) alkyl, in which the heterocyclic ringcontains one to three nitrogen atoms; or 5- or 6-membered aromaticheteromonocyclic(lower)alkyl, in which the heterocyclic ring containsone or two nitrogen atoms and one sulfur atom; and R⁵ iscarboxy;esterified carboxy selected from:lower alkoxycarbonyl, C₆ -C₁₀ar(lower)alkoxycarbonyl and C₆ -C₁₀ aroyl(lower) alkoxycarbonyl;amidated carboxy selected from:carbamoyl, N- orN,N-di(lower)alkylcarbamoyl, lower alkylcarbamoyl substituted by one ortwo substituents selected from carboxy and protected carboxy,N-(lower)alkyl-N-{carboxy- or protected carboxy (lower)alkyl}carbamoyl,C₆ -C₁₀ ar(lower)alkylcarbamoyl, carboxy- or protectedcarboxy-substituted C₆ -C₁₀ ar(lower)alkylcarbamoyl, C₃ -C₇cycloalkylcarbamoyl, N-{carboxy- or protected carboxy-substituted C₃ -C₇cycloalkyl(lower)alkyl}carbamoyl, lower alkylsulfonylcarbamoyl, C₆ -C₁₀arylsulfonylcarbamoyl, carboxy- or protected carboxy-substituted 5- or6-membered aromatic heteromonocyclic(lower)alkylcarbamoyl, in which theheterocyclic ring contains one to three nitrogen atoms, loweralkyleneaminocarbonyl, lower alkyleneaminocarbonyl substituted bycarboxy or protected carboxy, {lower alkyleneamino(lower)alkyl}carbamoylsubstituted by one to three substitutents selected from carboxy,protected carboxy and carbamoyl, morpholinocarbonyl, 5- or 6-memberedsaturated heteromonocycliccarbamoyl, in which the heterocyclic ringcontains one nitrogen atom and one oxygen atom, 5- or 6-memberedaromatic heteromonocycliccarbamoyl, in which the heterocyclic ringcontains one to three nitrogen atoms, 5- or 6-membered aromaticheteromonocycliccarbamoyl, in which the heterocyclic ring contains oneto two nitrogen atoms and one sulfur atom and may be substituted bylower alkyl, 9- or 10-membered benzene-condensed heterocyclic carbamoyl,in which the heterocyclic ring contains one to two nitrogen atoms andone sulfur atom, 5- or 6-membered saturatedhetermonocyclic(lower)alkylcarbamoyl, in which the heterocyclic ringcontains one nitrogen atom and one oxygen atom, 5- or 6-memberedaromatic heteromonocyclic(lower)alkylcarbonyl, in which the heterocyclicring contains one to three nitrogen atoms, carbazoyl,di(lower)alkylcarbazoyl; carboxy(lower)alkyl; or protectedcarboxy(lower)alkyl.
 4. The compound according to claim 3, whereinR¹iscarbamoyl; lower alkanoyl; amino(lower)alkanoyl; loweralkoxycarbonylamino(lower)alkanoyl; C₃ -C₇cycloalkylureideo(lower)alkanoyl; lower alkoxycarbonyl; C₃ -C₇cycloalkyl(lower)alkanoyl; C₃ -C₇ cycloalkylcarbonyl; PG,257 C₃ -C₇cycloalkyloxycarbonyl; benzoyl; naphthoyl; phenyl(lower)alkanoyl;naphthyl(lower)alkanoyl; amino-substituted phenyl(lower)alkanoyl; loweralkoxycarbonylamino-substituted phenyl(lower)alkanoyl;halophenyl(lower)alkanoyl; phenyl(lower)alkenoyl; phenylglyoxyloyl;phenyl(lower)alkylglyoxyloyl; pyridylcarbonyl;tetrahydropyridylcarbonyl; tetrahydroquinolylcarbonyl;tetrahydroisoquinolylcarbonyl; morpholinylcarbonyl;thiomorpholinylcarbonyl; indolylcarbonyl; piperazinylcarbonylsubstituted by one to three substituents selected from oxo and loweralkyl; pyridyl(lower)alkanoyl; morpholinylcarbonyl(lower)alkanoyl;phenyl(lower)alkylsulfonyl; N- or N,N-di(C₁ -C₁₀)alkylcarbamoyl;hydroxy(lower)alkylcarbamoyl; carboxy(lower)alkylcarbamoyl; loweralkoxycarbonyl(lower)alkylcarbamoyl; carbamoyl(lower)alkylcarbamoyl;({N- or N,N-di(lower)alkylcarbamoyl}(lower)alkylcarbamoyl; N-loweralkyl-N-{hydroxy(lower)alkyl}carbamoyl; N-loweralkyl-N-{di(lower)alkylcarbamoyl(lower)alkyl}carbamoyl; C₃ -C₁₀alkyleneaminocarbonyl;di(lower)alkylcarbamoyl(lower)alkyleneaminocarbonyl; N-lower alkyl-N-(C₃-C₇)cycloalkylcarbamoyl; mono- or di(C₃ -C₇)cycloalkylcarbamoyl;hydroxy- or di(lower)alkylcarbamoyl- ordi(lower)alkylcarbamoyl(lower)alkyl-substituted (C₃-C₇)cycloalkylcarbamoyl; C₃ -C₇ cycloalkyl(lower)alkylcarbamoyl;di(lower)alkylcarbamoyl-substituted C₃ -C₇cycloalkyl(lower)alkylcarbamoyl; di(lower)alkylcarbamoyl-substitutedphenyl(lower)alkylcarbamoyl; phenylcarbamoyl, in which the phenyl groupmay be substituted by one to three substituents selected from halogen,lower alkyl and lower alkoxy; pyridylcarbamoyl; N-loweralkoxycarbonylpiperidylcarbonyl morpholinyl(lower)alkylcarbamoyl; loweralkanoylcarbazoyl; lower alkyleneaminocarbamoyl; N-(C₃-C₇)cycloalkylcarbamoyl(lower)alkyl-carbamoyl; loweralkyleneaminocarbonyl(lower)alkylcarbamoyl;pyridyl(lower)alkylcarbamoyl; or oxo-substitutedhexahydroazepinylcarbamoyl; R⁴ ishydrogen; lower alkyl;amino(lower)alkyl; mono- or di- ortriphenyl(lower)alkoxycarbonylamin(lower)alkyl; carboxy(lower)alkyl;mono- or di- or triphenyl(lower)alkoxycarbonyl(lower)alkyl;phenyl(lower)alkyl; naphthyl(lower)alkyl; pyridyl(lower)alkyl;imidazlyl(lower)alkyl; or thiazolyl(lower)alkyl; R⁵ iscarboxy; loweralkoxycarbonyl; mono- or di- or triphenyl(lower)alkoxycarbonyl;benzoyl(lower)alkoxycarbonyl; carbamoyl; N- orN,N-di(lower)alkylcarbamoyl; lower alkylcarbamoyl substituted by one ortwo substituents selected from carboxy, lower alkoxycarbonyl, mono- ordi- or triphenyl(lower)alkoxycarbonyl and benzoyl(lower)alkoxycarbonyl;N-(lower)alkyl-N-{carboxy- or loweralkoxycarbonyl)(lower)alkyl}carbamoyl; phenyl(lower)alkylcarbamoyl;carboxy- or lower alkoxycarbonyl-substitutedphenyl(lower)alkylcarbamoyl; C₃ -C₇ cycloalkylcarbamoyl; carboxy(C₃-C₇)cycloalkyl(lower)alkylcarbamoyl; lower alkoxycarbonyl(C₃-C₇)cycloalkyl(lower)alkylcarbamoyl; lower alkylsulfonylcarbamoyl;phenylsulfonylcarbamoyl; carboxy- or lower alkoxycarbonyl-substitutedpyridyl(lower)alkylcarbamoyl; lower alkyleneaminocarbonyl; loweralkyleneaminocarbonyl substituted by carboxy or lower alkoxycarbonyl;{lower alkyleneamino(lower)alkyl}carbamoyl substituted by one to twosubstituents selected from carboxy, lower alkoxycarbonyl and carbamoyl;morpholinocarbonyl; morpholinylcarbamoyl; pyridylcarbamoyl;thiazolylcarbamoyl; lower alkylthiadiazolylcarbamoyl;benzothiazolylcarbamoyl; morpholinyl(lower)alkylcarbamoyl;pyridyl(lower)alkylcarbonyl; carbazoyl; di(lower)alkylcarbazoyl;carboxy(lower)alkyl; lower alkoxycarbonyl(lower)alkyl; orbenzoyl(lower)alkoxycarbonyl(lower)alkyl, and R₇ is hydrogen.
 5. Thecompound according to claim 4, whereinR¹ is N- or N,N-di(C₁-C₁₀)alkylcarbamoyl, N-lower alkyl-N-(C₃ -C₇)cycloalkylcarbamoyl, N- orN,N-di(C₃ -C₇)cycloalkylcarbamoyl,N-(lower)alkyl-N-{N,N-di(lower)alkylcarbamoyl(lower)alkyl}carbamoyl,phenylcarbamoyl, C₃ -C₁₀ alkyleneaminocarbonyl,{N,N-di(lower)alkylcarbamoyl56 (lower)alkylcarbamoyl orN-(lower)alkyl-N-{hydroxy(lower)alkyl}carbamoyl, R⁴ ispyridyl(lower)alkyl or phenyl(lower)alkyl, and R⁵ is carboxy, loweralkoxycarbonyl, carbamoyl or N- or N,N-di(lower)alkylcarbamoyl, and A ismethylene or --NH--.
 6. The compound according to claim 5, whereinR¹ isisopropylcarbamoyl, 2-methylbutylcarbamoyl, hepthylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl,diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl,pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, 3,5- or2,6-dimethylpiperidin-1-ylcarbonyl, hexahydro-1H-azepin-1-ylcarbonyl,octahydroazocin-1-ylcarbonyl orN-(1-dimethylcarbamoyl-2-methylpropyl)carbamoyl, R² is isobutyl, R³ isindol-3-ylmethyl, N-formylindol-3-ylmethyl, N-methylindol-3-ylmethyl,N-ethylindol-3-ylmethyl, N-propylindol-3-ylmethyl orN-isobutylindol-3-ylmethyl, R⁴ is 2-pyridylemthyl or benzyl, and R⁵ iscarboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl,ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl,N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl.
 7. A pharmaceuticalcomposition which comprises a compound of claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier orexcipient.
 8. A process for preparing a pharmaceutical composition whichcomprises admixing a compound of claim 1 or pharmaceutically acceptablesalts thereof with a pharmaceutically acceptable carrier or excipient.9. A method of treating endothelin mediated diseases which comprisesadministering a compound of claim 1 or pharmaceutically acceptable saltsthereof to human being or animals.